Os aka Uni ver sit y RIMD Re s e arch In s titute f or Microbial Dis e a s e s

2019-2020

Published by＞

Ofﬁce for Research Promotion
Research Institute for Microbial Diseases
Osaka University
3-1 Yamadaoka, Suita, Osaka 565-0871, Japan
Tel +81- 6 - 6879 - 8357
e-mail biken-pr@biken.osaka-u.ac.jp

http://www.biken.osaka-u.ac.jp/en/

2019-2020

Research Institute for Microbial Diseases (RIMD), Osaka University is aworld's foremost institute for basic biological researches including microbiology, immunology and oncology.
We dedicate to stimulate fundamental biological researches as a MEXT
Joint usage/research center.

1

Contents
Organization

4

Division of Infectious Disease

6

Department of Molecular Bacteriology
Department of Viral Infections
Department of Molecular Virology
Department of Immunoparasitology
Department of Infection Microbiology
Institute for Advanced Co-Creation Studies
Division of Host Defense

16

Department of Molecular Immunology
Dept of Immunochemistry
Division of Cellular and Molecular Biology

20

Department of Molecular Microbiology
Department of Oncogene Research
Department of Signal Transduction
Department of Cellular Regulation
Department of Homeostatic regulation
Genome Information Research Center

30

Department of Experimental Genome Research
Department of Genome Informatics
Department of Infection Metagenomics
Next-Generation Sequencing (NGS) Core Facility
Research Center for Infectious Disease Control

38

Department of Bacterial Infections

Message from the Director
In 1934, the Research Institute forMicrobial Diseases (RIMD), the first
institute attached to Osaka University,
was established for the study of microbial diseases. For more than 80 years
since its foundation, the RIMD hasconcentrated on basic researches in
infectious diseases, immunology, andoncology and made significant contributions to the control of infectious
diseases through the identification of
new pathogens, the elucidation ofpathogenesis of microbes, and thedevelopment of vaccines and diagnostics based on these basic researchfindings. In addition, the RIMD has
achieved an outstanding contribution in
the progress of life sciences throughthe discovery of oncogenes and cellfusion phenomena and the elucidationof innate immune system.
The RIMD is cer tified as the Joint
Usage/ Research Center by the Ministry of Education, Culture, Sports, Science and Technology Japan (MEXT).
In addition to the collaborative
research conducting in our facilities,
the RIMD is also responsible to support for international scientific community through the provision of the bacteria stored at our Pathogenic Microbes
Repository Unit. Faculties at the RIMD
are also af f iliated to the Graduate
Schools of Medicine, Frontier Biosciences, Science, and Pharmaceutical
Scienc es at Osaka Universit y andac c epted many graduate students
worldwide for contribution to the development of human resource in the next
generations.

The RIMD produces world-leading
research on infectious diseases frombasic research to clinical applications
through tight collaborations with
BIKEN, public interest incorporated
foundation engaged in development,
production and supply of a wide varietyof vaccines based on the researchfindings in the RIMD, and the Immunology Frontier Research Center (IFReC),
established by the great efforts of 4
researchers in the RIMD to develop
new research projects designed toclarify immune responses in a spatiotemporal manner in the body.
The RIMD will continue to dedicate
our efforts in the progress of the basic
research of infectious diseases, immunology, oncology, developmental biology, and cell biology based on the past
outstanding achievements, and to
focus on the development of young
researchers either in Japan or abroad
who are highly motivated to discoverand establish new scientific paradigms
by themselves.

Department of Virology
International Research Center for Infectious Diseases

41

Laboratory of Clinical Research on Infectious Diseases
Laboratory of Emerging Viral Diseases

Yoshiharu Matsuura D.V.M., Ph.D.

Pathogenic Microbes Repository Unit
Research Center for Mechanism and Regulation of Aging

44

Research Center for Infectious Disease Control

46

Director
Research Institute for Microbial Diseases
Osaka University

Yabumoto Department of Intractable Disease Research
Department of Molecular Protozoology
Thailand-Japan Research Collaboration Center

50

Section of Bacterial Infections
Section of Viral Infections
Section of Bacterial Drug Resistance Research
Section of Antiviral Research
Mahidol-Osaka Center for Infectious Diseases
BIKEN Innovative Vaccine Research Alliance Laboratories

56

Vaccine Creation Project
Mucosal Vaccine Project
Vaccine Dynamics Project2

Animal Resource Center for Infectious Diseases

60

Ofﬁce for Research Promotion

61

Common Research Facilities

62

About RIMD

64

For Students and Researchers who wants to study in RIMD

72

Grad Students Studying in RIMD

74
3

Organization

To overcome infectious diseases

Research Center for Infectious Disease Control
SpecialResearch
Facilities

Resear ch Institute f or Micr obial
Diseases (RIMD) was established as a
research center for microbiology,● Department of Bacterial Infections

Iida Lab● Department of Virology

Kobayashi Lab

To understand our body system from genetic information

Genome Information Research Center

immunology and oncology in 1934. We
have performed outstanding
researches in these fields and we also

● Department of Experimental Genome Research

Ikawa Lab

contribute extensively to growth in the● Department of Genome Informatics

Daron Labbasic sciences in Japan thorough● Department of Infection Metagenomics

Iida Labadvanced research and the● Laboratory of Genome Research

Miwa Labdevelopment of human resources.

● Network Administration Ofﬁce

Now, we are also developing new
research fields such as geneengineering, genome research andalways exploring breakthrough inbiological science.

To develop new therapeutic approaches to infectious diseases

Research
DivisionsInternational Research Center for Infectious Diseases
To explore the pathogenesis of microbes● Laboratory of Clinical Researchon Infectious Diseases

Division of Infectious Disease● Dept. of Molecular Bacteriology

Horiguchi Lab● Dept. of Viral Infections

Shioda Lab● Dept. of Molecular Virology

Matsuura Lab● Dept. of Infection Microbiology

Mimuro Lab● Dept. of Immunoparasitology

Yamamoto Lab● Institute for Advanced Co-Creation

Okamoto Lab

Studies

To explore the mechanisms that protect against microbes● Department of Molecular Immunology

Yamasaki Lab● Dept of Immunochemistry

Arase LabTo explore regulatory mechanisms in cancer cells

Division of Cellular and Molecular Biology● Department of Molecular Microbiology

Hara Lab● Department of Oncogene Research

Okada Lab● Department of Signal Transduction

Takakura Lab● Department of Cellular Regulation

Miki Lab● Department of Homeostatic regulation

Ishitani Lab

Common Research Facilities

Administration● Central Laboratory● General Affairs Section

for Biological Hazardous Microbes● Radioisotope Laboratory● Accounting Section● Research Cooperation Section

Ofﬁce for Research Promotion
4● Laboratory of Emerging Viral Diseases

Iwasaki Lab● Laboratory of Pathogen Detection and Identiﬁcation

Nakamura Lab● Pathogenic Microbes Repository Unit

Animal Resource Center for Infectious Diseases
Research Center for Mechanism and Regulation of Aging● Division of Aging Model Organism● Division of Cellular Senescence

Division of Host Defense● Central Instrumentation Laboratory

Kamitani Lab

Thailand-Japan Research Collaboration Center● Section of Bacterial Infections● Section of Bacterial Drug Resistance Research● Section of Viral Infections● Section of Antiviral Research● Mahidol-Osaka Center for Infectious Diseases

Endowed Chair● Yabumoto Department ofIntractable Disease Research● Department of Molecular Protozoology

Kinoshita Lab
Horii LabTo develop novel vaccines with high safety and efﬁcacy

BIKEN Innovative Vaccine Research Alliance Laboratories● Vaccine Creation Project

Yoshioka Lab● Mucosal Vaccine Project

Sato Lab● Vaccine Dynamics Project

Aoshi Lab

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Division of Infectious Disease

Department of
Molecular Bacteriology
Some pathogenic bacteria cause specific disease
symptoms including flaccid/spastic paralyses,
paroxysmal coughing, skin exfoliation, and osteogenesis imperfecta, besides general symptoms
such as fever and inflammation. Our major
questions are as to how these specific symptoms
appear in response to bacterial infections or whatkinds of bacterial virulence factors are involved inthem. We hope that we will understand the nature ofbacterial infections by answering these questions.

●To understand the mechanism of infection●Analyzing the structure-function relationshipof bacterial protein toxins.

Bordetella pertussis, which is one of our research subjects
is a representative pathogenic bacteria of Bordetella andcauses whooping cough. In addition to B. pertussis, B.
parapertussis and B. bronchiseptica are categorized in thegenus Bordetella. Although these pathogenic organisms
share homologous virulence factors and commonly cause
respiratory infections with characteristic coughing, their hostspecificities and the course of disease manifestation arequite different: B. pertussis is a strict human pathogen causing
the acute disease whereas B. bronchiseptica infects a wide
range of mammals and causes chronic infections. We aretrying to understand what determines host specificities anddistinct disease manifestations in Bordetella infections.
Understanding the molecular mechanism by which thebacteria cause coughing in hosts is our another goal of the
Bordetella research.

Bacterial protein toxins cause a variety of specific symptoms manifested in bacterial infections. Many bacterial
protein toxins are essentially multifunctional biomolecules,
which travel in a host body, bind to target molecules or cells,
and modify target molecules with high specificity. Some
bacterial toxins are known as the most poisonous substances on the earth. We are analyzing the structure-function
relationship of these bacterial protein toxins to understandhow they exert such powerful toxicities on target cells andintoxicated animals. We believe that these results should
give an insight into the mechanism causing specific symptoms observed in bacterial infections.
To achieve the above-mentioned goals, we are conducting
the research work by using every experimental techniquebased on bacteriology, molecular and cellular biology,
biochemistry, medical and veterinary science.

Staff
Asst. Prof. : Yukihiro Hiramatsu ／Postdoc. : Takashi Nishida ／Grad. Student 3

Yasuhiko Horiguchi
Professor
Dr. Horiguchi received his Ph.D. from Osaka Prefecture University in 1987. After working at the Kitasato
Institute for 3 years, he has worked for RIMD since1990. He took his positon as Postdoc in 1990, a Research Associate in 1992, an Associate Professor
in 1998. He was appointed current position in 2001.

Publication(1)The Eukaryotic Host Factor 14-3-3
Inactivates Adenylate Cyclase Toxins of
Bordetella bronchiseptica and B.
parapertussis, but not B. pertussis.
Fukui-Miyazaki A., et al mBio (2018)
9:49–15.
(2)Ectopic Expression of O Antigen in
Bordetella pertussis by a Novel
Genomic Integration System. Ishigaki
K., e tal. mSphere (2018)
3:e00417–17–11.
6(3)Protective effects of in vivo-expressed
autotransporters against Bordetella
pertussis infection. Suzuki K., et al.
Microbiology and Immunology (2017)61:371–379.
(4)The bvg-repressed gene brtA, encoding
bioﬁlm-associated surface adhesin, isexpressed during host infection by
Bordetella bronchiseptica. Nishikawa S.,
et al. Microbiology and Immunology(2016) 60:93–105.

(5)Detection of genes expressed in
Bordetella bronchiseptica colonizing rat
trachea by in vivo expressed-tag
immunoprecipitation method. Abe H., etal. Microbiology and Immunology (2015)59:249–261.
(6)Polymorphisms influencing expressionof dermonecrotic toxin in Bordetella
bronchiseptica. Okada K., et al. PLoS
ONE (2015) 10:e0116604.

7

Division of Infectious Disease

Department ofViral Infections
Viruses are simple organisms composed ofproteins, nucleic acids, and, in some cases,
lipids. Nevertheless, they interact withseveral host factors and ultimately cause
disease in humans. Our laboratory focuseson the molecular mechanisms underlying
viral diseases, including human immunodeficiency virus (HIV).

Staff
Assoc. Prof.：Emi E. Nakayama ／●Antiviral host factors and their application
to a cure for HIV infection●Analysis of HIV-1 genome RNA dimerization

HIV does not establish a productive infection in any monkey
other than the chimpanzee. Also, the sensitivity of HIV
infection and rate of disease progression vary from individual
to individual. To date, several anti-HIV host restriction factors,
including TRIM5α and TRIMCyp, have been identified as
responsible for these phenomena. Currently, we are trying toelucidate the molecular mechanism(s) underlying the anti-HIV
activity of these factors. We also aim to cure HIV infection by
establishing novel reproductive medicine-based strategies,
including iPS cells from HIV patients.

The genome of retroviruses such as HIV-1 always exists as
a dimer; genome dimerization plays an important role atvarious stages of the viral life cycle, including genome
packaging and reverse transcription as well as the genome
recombination processes involved in viral diversification.
Therefore, genome dimerization is a novel target for
anti-HIV therapies. We are currently analyzing computer-assisted structural models of HIV-1 Dimer Initiation Sequences, which are the most important factors involved in genome
dimerization, to get a more complete picture of HIV genome
dimerization. We are also analyzing genome recombination
in HIV-1 by constructing a novel system to measure recombination efficiency.

●Human genome analysis of HIV-associatedneurocognitive disorders

Undergrad. Student 1 ／Grad. Student 1

Despite successful antiretroviral therapy, nearly a quarter of
HIV patients develop mild-to-severe neurocognitive disorders(HAND). We aim to undertake genome analysis of HAND
patients to elucidate the underlying molecular mechanisms,
thereby developing therapeutic strategies to treat/prevent thisdisease.

Tatsuo Shioda
Professor
Dr. Shioda obtaind his B. Sc. from the University of Tokyo in 1982 and his Ph.D. form thesame institution in 1990. After working at theInstitute of Medical Science in the Universityof Tokyo and University of California San Francisco, he was appointed as Associate Professor in 1997. He took his current position as a
Professor of RIMD in 2000.
Fig. 2.Newly identified structure of DIS.
A. Comparison of the current model(brown) with the previously proposedmodel (yellow). B. Structure in a dimericform. The newly identified model shows
more extended DIS structure possibly
allowing stronger molecular interaction.

Publication

8(1) Naturally Occurring Mutations in HIV-1
CRF01_AE Capsid Affect Viral
Sensitivity to Restriction Factors.
Nakayama E.E., et al., AIDS Res Hum
Retroviruses. (2018)
doi:10.1089/AID.2017.0212.

(3) Genome-wide association study ofHIV-related lipoatrophy in Thai patients:
Association of a DLGAP1 polymorphism with fat loss. Uttayamakul S., etal. AIDS Res Hum Retroviruses. (2015)
Aug;31(8):792-6.

(5) A Single-Nucleotide Polymorphism in
ABCC4 Is Associated with Tenofovir-Related Beta2-Microglobulinuria in
Thai Patients with HIV-1 Infection.
Likanonsakul S., et al. PLoS One (2016)
Jan 25;11(1):e0147724.

(2) SL1 revisited: functional analysis of
the structure and conformation of
HIV-1 genome RNA. Sakuragi S.,
Retrovirology. 2016 Nov 11;13(1):79.

(4) Impact of TRIM5α in vivo. Nakayama
E.E., et al. AIDS. (2015) Sep 10;29(14):1733-43.

(6)Novel mutant human immunodeﬁciency virus type 1 strains with high degreeof resistance to cynomolgus macaque
TRIMCyp generated by randommutagenesis. Sultana T., et al. J Gen
Virol. (2016) Apr;97(4):963-76. a

Fig. 1.Host factors involoving in early replication steps of HIV

9Division of Infectious Disease

Department of
Molecular Virology
Viruses “know” cells better than humanbeings and have evolved to replicate inliving cells. We are working to understandthe molecular mechanisms underlying theinterplay between viruses and host cells
through research on hepatitis viruses,
flaviviruses, and insect viruses.

Staff
Assoc. Prof. : Yusuke Maeda ／Assoc.Prof.：Takasuke Fukuhara ／Asst. Prof.：Chikako Ono ／Undergrad. Student 3 ／ Grad.
Student 6●Molecular biology of hepatitis viruses●Development of baculoviral vectors

Hepatitis C virus (HCV) infects over 170 million individuals
worldwide and is one of the most common etiologic agents ofchronic liver disease, including liver cirrhosis and hepatocellular carcinoma (HCC). Although novel innovative anti-HCV
drugs that act directly on viral proteins have achieved asustained virological response in hepatitis C patients,
drug-resistant viruses emerge easily. Therefore, host factors
necessary for HCV replication are ideal targets for the development of new therapeutics for chronic hepatitis C; suchdrugs will lessen the possibility of drug-resistant breakthrough viruses emerging because the frequency of mutation
is much lower than that in the viral genome.

Development of viral vectors capable of safely transducing
foreign genes into target cells is essential for future genetherapy. We are working on developing the insect baculovirus, Autographa californica nucleopolyhedro virus, as aversatile viral vector for gene delivery. Baculovirus is capableof entering a variety of mammalian cells and facilitates expression of foreign genes under the control of mammalianpromoters; however, the viral genome does not replicate. We
are working on developing viral vectors that have the advantages and characteristics of baculovirus.

Upon infection with HCV, viral RNA is directly translated into
viral proteins. Viral RNA replicates in the cytoplasm using
various host factors and organelles. Viruses replicate in living
cells, and some of them, including HCV, are pathogenic to
the host. We are focusing on trying to understand the molecular mechanisms underlying the interaction between thevirus and host by identifying the host factors involved in the
propagation and pathogenicity of HCV. We have shown thatthe HCV core protein participates not only in the assembly ofviral particles but also in the development of liver steatosis
and HCC. We have also shown that host proteins, including
molecular chaperones and apolipoproteins, participate inviral replication and in the formation of infectious particles.
Novel therapeutic agents targeting the host factors crucial for
propagation and pathogenesis of HCV could be available if
we can elucidate the molecular mechanisms underlying
infection and replication of HCV. We are also working on
hepatitis B virus and Japanese encephalitis virus, also members of the Flaviviridae.

Yoshiharu Matsuura
Professor
Dr. Matsuura received his PhD from Hokkaido University in 1986 and worked at Research Institute of Daiichi Seiyaku Co. Ltd
for . He was appointed Professor in RIMD in
2000 after working at NERC Institute of Virology in Oxford University as a postdoctoral
fellow and at the National Institute of Infectious Diseases as a head of Laboratory of
Hepatitis Viruses in Department of Virology
II. He serves as Director of RIMD from 2015.

Publication(1) Infection with flaviviruses requires
BCLXL for cell survival. Suzuki T., et al.,PLoS Pathog. (2018) 14(9):e1007299.
(2) Characterization of SPP inhibitors
suppressing propagation of HCV andprotozoa. Hirano J etal. Proc Natl Acad
Sci U S A. 2017 Dec 12;114(50):E10782-E10791.

10(3) Host-derived apolipoproteins playcomparable roles with viral secretory
proteins Erns and NS1 in the infectious
particle formation of Flaviviridae.
Fukuhara T et al., PLoS Pathog. 2017
Jun 23;13(6):e1006475.

(5) TRC8-dependent degradation ofhepatitis C virus immature core protein
regulates viral propagation andpathogenesis. Aizawa S. & Okamoto T.,
et al. Nat. Commun. (2016),
doi: 10.1038/ncomms11379.

(4) Characterization of
miR-122-independent propagation of
HCV. Ono C, et al. PLoS Pathog. 2017
May 11;13(5):e1006374.

(6) Lipoprotein receptors redundantly
participate in entry of hepatitis C virus
Yamamoto S. & Fukuhara T.,et al. PLoS
Pathog. (2016), doi: 10.1371/journal.
ppat.1005610.
11

Division of Infectious Disease

Dept. of Immunoparasitology
In our immunoparasitology laboratory, we use theapicomplexan protozoan parasite Toxoplasma
gondii as a model for exploring host defense
systems and pathogenesis. Our research goal is toelucidate the molecular mechanisms underlying theinterface between the host and pathogen.

Staff

Toxoplasma gondii is an obligatory intracellular protozoan
pathogen that causes lethal toxoplasmosis in humans and animals. One third of the global population is thought to be infected with this pathogen, making it the “most successful parasite.”T. gondii infects virtually all nucleated cells in warm-blooded animals. The parasite forms a special membranous structure
called a “parasitophorous vacuole (PV).” The host-parasite interaction takes place through the PV. In response to T. gondii,
the host immune system produces inflammatory cytokines
such as interleukins, chemokines, and interferons. Interferon-γ (IFN-γ) is the most important host factor for inducing anti-T. gondii responses, which suppress and kill the parasites.
One of the main projects in our laboratory is to identify the
IFN-γ-induced anti-T. gondii host defense mechanisms involved in innate and adaptive immunity. Recently, we foundthat IFN-γ-inducible GTPases called GBPs are important forT. gondii PV disruption, and that their function in anti-T. gondii
responses requires autophagy proteins; this suggests an unexpected link between IFN-γ-induced immunity and autophagic pathways.

Assoc. Prof. ：Miwa Sasai ／On the other hand, virulent T. gondii suppress IFN-γ-induced
host immunity and even manipulate host immune cells to maximize the virulence of the parasite. Another main project in ourlaboratory is to identify novel virulence mechanisms used by
T. gondii. For example, we recently showed that a T. gondii-secreting virulence factor, GRA6, directly activates the host transcription factor NFAT4 to induce chemokines and recruit neutrophils to eradicate the parasite. Thus, our laboratory is focusing on host-parasite interactions via immunoparasitologicalmechanisms.

Dense granule

Asst. Prof. : MA JISU ／Postdoc.：Masaaki Okamoto ／Grad. Student 4

Rhoptry

Masahiro Yamamoto
Professor
Received B. Sc. from the University of Tokyo(2001) and Ph.D. from Osaka University(2006). Promoted to an assistant professor(2006), an associate professor (2010) at thegraduate school of medicine in Osaka University, an independent associate professor(2012) at RIMD in Osaka University. Appointed current position as a Professor of RIMD in2013.

Fig. 1. Toxoplasma gondii
Pathogenic proteins are secreted from Dense granules and Rhoptry.

Fig. 2. Toxoplasma gondii (green) proliferating inside macrophages (red).

Publication(1)Inducible Nitric Oxide Synthase Is a Key
Host Factor for Toxoplasma
GRA15-Dependent Disruption of theGamma Interferon-Induced
Antiparasitic Human Response. Bando
H., et al. MBio. (2018) 9(5).
(2) Essential role for GABARAP autophagy
proteins in interferon-inducible
GTPase-mediated host defense. Sasai
M., et al., Nat Immunol. (2017) 18(8):899-910.
12(3) p62 plays a speciﬁc role ininterferon-γ-induced presentation of a
Toxoplasma vacuolar antigen. Lee Y., etal. Cell Rep. (2015) 13:223-33.
(4) RabGDIα is a negative regulator ofinterferon-γ-inducible
GTPase-dependent cell-autonomous
immunity to Toxoplasma gondii.
Ohshima J., et al. Proc Natl Acad Sci
USA. (2015) 112:E4581-90.

(5) Selective and strain-speciﬁc NFAT4
activation by the Toxoplasma gondii
polymorphic dense granule protein
GRA6. Ma J.S., et al. J Exp Med. (2014)
211:2013-32.
(6) A cluster of interferon-γ-inducible p65
GTPases plays a critical role in hostdefense against Toxoplasma gondii.
Yamamoto M., et al. Immunity (2012)
37:302-13.

Fig. 3. Gate-16 (red) is required for antimicrobial host defense throughcytosolic distribution of GTPase (green).
GTPase punctae are colocalized with Gate-16 (right fig.) throughout thecell. However, expression of mutant Gate-16 leads to GTPase aggregationand hampers immune response against pathogens.
13

Division of Infectious Disease

Division of Infectious Disease

Department of
Infection Microbiology
Bacteria-gut interplay and the host immune
response are the most critical issues indetermining the fate of bacterial infections
and the severity of the diseases. Our grouphas been studying the pathogenesis of
mucosal infectious bacteria, such as Helicobacter pylori, Shigella, enteropathogenic
Escherichia coli, and Streptococcus
pyogenes, by defining the molecular andcellular mechanisms of infections and theroles of pathogenic factors as well as thehost factors in infections.

Institute for Advanced
Co-Creation Studies

Staff
Asst. Prof.：Ryota Otsubo ／Postdoc：Takahito Sanada ／Postdoc：Ryo D Kinoshita ／Grad. Student 2

Dr. Mimuro received her Ph.D. from The Universityof Tokyo in 2004. She became Assistant professor
at the Institute of Medical Science, The Universityof Tokyo in 2005 and worked for the same institution. She was appointed Associate Professor in
RIMD in 2017.

Toru Okamoto
Professor

教授

Dr. Okamoto received his Ph.D. from Osaka University in 2006. Thereafter he worked as a postdoctoral fellow at RIMD in 2006, a researcher at Walterand Eliza Hall Institute of Medical Research in2008. He was appointed as a current position from2019 after working as an assistant professor(2012) and an associate professor (2017) at Research Institute for Microbial Diseases.

Publication(4)The immune receptor NOD1 and kinase RIP2 interact withbacterial peptidoglycan on early endosomes to promote
autophagy and inflammatory signaling. Irving A.T., et al., Cell
Host Microbe. (2014) 15(5):623-35

In the Mimuro laboratory, researchers are exploring the pathogenesis of mucosal infectious bacteria, including H. pylori, Shigella,enteropathogenic E. coli, and S. pyogenes.
H. pylori transports effector proteins and other molecules into hostepithelial cells via a Type IV secretion system and/or outermembrane vesicles. Researchers are studying how these effectors
cause diseases such as gastritis, gastric ulcers, and cancer. They
are also trying to elucidate the mechanisms that enable long-term
infection of H. pylori in the stomach. In addition, researchers arefocusing on the molecular mechanisms in the host that protect
against infectious bacteria. The expected output of their research
will not only shed further light on bacterial pathogenesis, but also
provide a new paradigm in microbiology, cell biology, immunity, andpathology, and strengthen the molecular basis for developing
diagnostic products, vaccines, animal models, and therapeutic
agents.

(1)USP15 Participates in Hepatitis C Virus Propagation throughRegulation of Viral RNA Translation and Lipid Droplet
Formation. Kusakabe S. & Okamoto T. et al., J Virol. 2019
Mar 5; 93(6). pii:e01708-18(2)Infection with flaviviruses requires BCLXL for cell survival.
Suzuki T. & Okamoto T., et al. PLoS Pathog. 2018 Sep 27; 14(9):e1007299.

●Pathogenicity of hepatitis viruses

Infection with Hepatitis C virus (HCV) induces chronic
infection and leads to develop steatosis, cirrhosis andhepatocellular carcinoma. Among 10 viral proteins, HCV
core protein forms a viral particle and induces steatosis andhepatocellular carcinoma in transgenic mice model. It
suggests that core is strongly associated with liver diseases
in chronic hepatitis C. Our research is focusing on maturation of core protein by signal peptide peptidase (SPP) and its
maturation is essential for formation of viral particle anddevelopment of liver diseases. We would like to clarify why
maturation of HCV core is needed for its function, especiallyliver diseases.

●Pathology of mosquito-borne flavivirus anddevelopment of new antiviral drugs
Infectious diseases by infection with mosquito-borne flavivirus, one of which is microcephaly by infection with Zika

(3)Characterization of SPP inhibitors suppressing propagationof HCV and protozoa. Hirano J. & Okamoto T., et al. Proc Natl
Acad Sci USA. 2017 Dec 12;114 (50):E10782-E10791.
(4)TRC8-dependent degradation of hepatitis C virus immature
core protein regulates viral propagation and pathogenesis.
Aizawa S. & Okamoto T., et al. Nat. Commun. 2016 May 6; 12(5): e1005610

virus, have become a serious problem worldwide. Mosquito-borne
flavivirus spreads infection through blood feeding of virus-infectedmosquito. While host ranges of virus infection are generally limited,mosquito-borne flavivirus can propagate mosquito and mammals.
We study how mosquito-borne flavivirus infects mosquito andmammals and how transmission between mosquito and mammals
is associate to development of diseases.
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Publication

14

Asst. Prof.：Tatsuya Suzuki

Subsomwong ／Associate professor(2)Characterization of morphological conversion of
Helicobacter pylori under anaerobic conditions. Hirukawa S.,
et al. Microbiol. Immunol. (2018) 62(4);221-28

Staff
Staff

Guest Researcher : Phawinee

Hitomi Mimuro(1)Shigella effector IpaH4.5 targets 19S regulatory particle
subunit RPN13 in the 26S proteasome to dampen cytotoxic
T lymphocyte activation. Otsubo R., et al. Cell Microbiol.
(2018) e12974

Our research is focusing on pathogenesis ofinfection with hepatitis viruses such as
Hepatitis C virus and Hepatitis B virus andwith mosquito-borne flaviviruses such as
Japanese encephalitis virus (JEV), Dengue
virus (DENV) and Zika virus (ZIKV). It still
remains unclear how these viruses induce avariety of diseases in hosts. We aim to study
to understand molecular mechanisms ofpathogenicity of virus infection throughmolecular biology and animal models.

15

Division of Host Defense

Department of
Molecular Immunology
Our bodies are continuously exposed to external and internal
insults caused by infection and tissue damage, most of which
are primarily sensed by immune receptors to maintain tissue
homeostasis. However, the molecular mechanism by whichthese receptors discriminate diverse insults to elicit suitable
immune responses remains elusive. We have found that C-type
lectin receptors can sense both damaged self and non-self
pathogens (Figure 1). Recently, we also showed that clusteredC-type lectin receptors, Mincle, MCL, Dectin-2 and DCAR, canrecognize mycobacteria through their unique glycolipids
possessing adjuvant activity (Figure 2). Our objective is toillustrate the principle behind the regulation of immune responses through C-type lectin receptors in physiological and pathological settings. Based on these results, we also aim to design
new methods to efficiently elicit or modulate immune responses.
To this end, our research is focusing on the following axes:
1) Immune sensing of pathogens and damaged-self via C-type
lectin receptors.
2) Unique T cell responses induced by self peptides.
3) Atypical T cell subsets critical for autoimmune diseases.

Staff
Asst. Prof.：Eri Ishikawa ／Asst. Prof.：Chihiro Motozono ／Postdoc.：Kenji Toyonaga ／Postdoc.：Xiuyuan Lu ／ Guest
Grad. Student 12●C-type lectin receptors (CLRs) sense both“non-self pathogens” and “damaged self”.
CLRs are involved in innate immunity; however, this family
exhibits higher diversity and ligand specificity than other innate
immune receptor families such as Toll-like receptors due to thewider variety of genes [Fig.1]. CLRs recognize pathogen-associated molecular patterns. We showed that Mincle (macrophage-inducible C-type lectin) recognizes the glycolipid TDM(trehalose-6,6'-dimycolate), a component of the Mycobacterium tuberculosis cell wall. This CLR acts as a sensor to trigger
the immune response through a signaling pathway that involves
FcRγ and CARD9, among other components. We also identified the ligands through which the CLRs MCL (macrophage
C-type lectin), Dectin-2 (dendritic cell-associated C-type lectin-2), and DCAR (dendritic cell immunoactivating receptor) recognize M. tuberculosis and other pathogens, and elucidated
some of the mechanisms by which they induce immune
responses.

In addition, in a recent study, our group shed light on the function of Mincle in the recognition of endogenous ligands. Mincle
can bind to β-glucosylceramide, a glycolipid that is released byhost cells after damage. Thus, Mincle not only detects pathogens or foreign ligands, but also endogenous molecules
released by damaged cells to activate the immune system andthe response to “danger” situations.
We are presently investigating in further detail the recognitionof both self and non-self ligands by this family of receptors andtheir role in immunity [Fig.2].

●Self ligands are recognized
by T cell receptors (TCRs) andplay an important role in T cell persistence●Novel T cell subsets contributeto autoimmune diseases

T cells pass various selections of their TCRs before they
are released from the thymus into the periphery. TCRs thatweakly bind to self ligands cause T cell retention, and the signaling cascades induced by self ligands are important for T
cell persistence but do not lead to T cell activation. Our objective is to clarify the recognition of “self” by TCRs and the distinct signals transduced by the same TCR upon stimulation
with self and non-self ligands.

Recent evidence has shown that novel T cell subsets are
responsible for autoimmune phenotypes that are comparablewith human disorders. We are interested in the ligands thatare recognized by these pathogenic T cells and the mechanisms via which the diseases develop. Based on the analysisof the corresponding subsets in human, we aim to design
new methods to diagnose and treat autoimmune diseases.

Fig. 1. Various immune responses triggered by Mincle

Fig. 2. Cooperative function of CLRs against mycobacteria

Sho Yamasaki
Professor
Dr. Yamasaki received his Ph.D. from Kyoto
University in 1999. After working at Mitsubishi
Chemical Corporation and Chiba University
Graduate School of Medicine, he worked for
Research Center for Allergy and Immunology,
RIKEN from 2004 to 2009. He was appointed
as Professor in Medical Institute of Bioregulation, Kyushu University in 2009. He took his
current position at RIMD from 2017.

Publication(1) Lipoteichoic acid anchor triggers
Mincle to drive protective immunity
against invasive group A
Streptococcus infection.I mai T., et al.
Proc. Natl. Acad. Sci USA. (2018)
115:E10662-71.
(2) Intracellular metabolite
β-glucosylceramide is an endogenous
Mincle ligand possessing
immunostimulatory activity. Nagata M.,
et al. Proc. Natl. Acad. Sci. USA. (2017)
114:E3285-94
16(3) Protein kinase D regulates positive
selection of CD4(+) thymocytes
through phosphorylation of SHP-1.
Ishikawa E., et al. Nat. Commun. (2016)
7:12756.
(4) C-type lectin receptor DCAR recognizes
mycobacterial phosphatidyl-inositol
mannosides to promote a Th1
response during infection. Toyonaga K.,
et al. Immunity. (2016) 45:1245-57.

(5) Dectin-2 is a direct receptor for
mannose-capped lipoarabinomannanof mycobacteria. Yonekawa A., et al.
Immunity. (2014) 41:402-13.
(6) C-Type lectin MCL is an FcRγ-coupled
receptor that mediates theadjuvanticity of mycobacterial cord
factor. Miyake Y., et al. Immunity. (2013)
38:1050-62.

17

Division of Host Defense

Dept of Immunochemistry
We have been studying interactions between
pathogens and various paired receptors. In
addition, we found that MHC class II molecules
function as molecular chaperones to transportmisfolded proteins to the cell surface. Analyses of
misfolded proteins transported to the cell surface
revealed that they are involved in autoimmune
diseases by acting as a target for autoantibodies.

●Interaction between immune receptors andpathogens●Misfolded proteins complexed with MHC
class II molecules trigger autoimmune disease

Immune cells express “paired” activating and inhibitory
receptors that are highly homologous. The inhibitory receptors recognize self-antigens and downregulate immune
response to the self. On the other hand, we found that someinhibitory receptors are used by pathogens for immune
evasion (Fig. 1). By contrast, we found that LILRA2, anorphan activating receptor expressed on human myeloid
cells, recognizes abnormal immunoglobulins cleaved by
microbial proteases but not normal immunoglobulins.
Because immunoglobulins are important for host defense,
their degradation is very dangerous in terms of immunity(Fig. 2). In this way, paired receptors play an important role
not only in immune regulation but also in host defense
against pathogens.

Allelic polymorphisms in MHC class II molecules arestrongly associated with susceptibility to many autoimmune
diseases. However, it is unclear how MHC class II molecules are involved in autoimmune disease susceptibility. We
found that misfolded cellular autoantigens are rescued fromprotein degradation by MHC class II molecules. Furthermore, we found that misfolded proteins complex with MHC
class II molecules and become targets for autoantibodies.
Autoantibody binding to misfolded proteins that are transported to the cell surface by MHC class II molecules
correlated strongly with susceptibility to autoimmune disease,suggesting that misfolded proteins, which normally would
not be presented to the immune system, can be targets for
autoantibodies by acting as “neo self” antigens, which are
involved in the pathogenicity of autoimmune diseases(Fig.3).

Fig. 1.
Inhibitory receptors play an important role in immune regulation,
whereas pathogens exploit inhibitory receptors for immune evasion. We found malaria parasite has a mechanism to suppress
the host immune response by using an inhibitory receptor, LILRB1, contributing to the pathogenesis of severe malaria.

Fig. 2. Activating paired receptors play a role in host defense
against bacterial infection
Activating paired receptor, LILRA2, recognizes immunoglobulin cleaved by bacterial protease activate innate immune cells(Hirayasu et al. Nat. Microbiol. 2016).

Staff
Assoc. Prof.：Tadahiro Suenaga ／Asst. Prof.：Masako Kohyama ／Postdoc.：Kazuki Kishida ／Undergrad. Student 3 ／Grad. Student 9

Hisashi Arase (concur.)Professor
Prof. Arase received M.D. from Hokkaido University School of Medicine at 1990 and received
Ph.D from Hokkaido University at 1994. Thereafter he worked as an assistant professor at
Chiba University School of Medicine (1994), a
research fellow at University of California San
Francisco (2000), an associate professor at
Chiba University (2002) and an associate professor at Research Institute for Microbial Diseases (2004). he is working as current position
from 2006.

Publication(1) Immune evasion of Plasmodium
falciparum by RIFIN via inhibitory
receptors. Saito F et al. Nature (2017)
552:101–105. Saito F., et al.,
(2) LILRA2 is an innate immune sensor for
microbially cleaved immunoglobulins.
Hirayasu K., et al. Nature Microbiology.
(2016) 6:16054.
doi: 10.1038/nmicrobiol.2016.54.

18(3) Autoantibodies to IgG/HLA class II
complexes are associated withrheumatoid arthritis susceptibility. Jin
H., et al. Proc. Natl. Acad. Sci. USA.
(2014) 111: 3787-92.

(5) Myelin-associated glycoprotein
mediates membrane fusion and entryof neurotropic herpesviruses. SuenagaT., et al. Proc. Natl. Acad. Sci. USA(2010) 107:866-71.

(4) Neutrophil inﬁltration during
inflammation is regulated by PILRα via
modulation of integrin activation. WangJ., et al. Nat. Immunol. (2013) 14:34-40.

(6) PILRα is a herpes simplex virus-1 entry
co-receptor that associates withglycoprotein B. Satoh T., et al. Cell
(2008) 132:935-44.

Fig. 3. Misfolded proteins complexed with MHC class II molecules aretargets for autoantibodies.
Misfolded cellular proteins are transported to the cell surface without
being processed to peptides by associating with MHC class II moleculesin the ER. Furthermore, misfolded proteins complexed with MHC class
II molecules encoded by disease-susceptible alleles are specificallyrecognized by autoantibodies. This suggests that misfolded proteinscomplexed with MHC class II molecules are natural autoantigens for
autoantibodies, which affect susceptibility to autoimmune diseases(Arase Adv. Immunol. 2016).

19

Division of Cellular and Molecular Biology

Department of
Molecular Microbiology
It has become apparent that aging has a major
impact on the incidence of cancers. However, theunderlying mechanisms are unclear. We think that
cellular senescence plays a key role. In ourlaboratory, we are aiming to understand the roles
and mechanisms of cellular senescence in vivo.
We believe that understanding the molecularmechanisms underlying cellular senescence invivo will provide valuable insight into the development of aging-associated diseases such as
cancer, and open up new possibilities for theircontrol.

●Exploring the physiological roles andmechanisms underlying cellular senescencein vivo
Cellular senescence is the state of irreversible cell cycle
arrest that can be induced by a variety of potentially oncogenic stimuli and has, therefore, long been considered tosuppress tumorigenesis. We reported that p16INK4a andp21Waf1/Cip1, both cyclin-dependent kinase inhibitors, play
crucial roles in both the onset and establishment of cellularsenescence in cell culture and in mouse models. Recently,
we generated transgenic mice expressing firefly luciferase
under the control of the p16INK4a or p21Waf1/Cip1 gene promoters. Using these senescence response reporter mice in
combination with knockout mice, we are investigating thetiming and, hence, the likely roles and mechanisms, ofcellular senescence in vivo.

Staff●Understanding the molecular mechanisms
underlying inflammatory diseases induced
by senescence-associated secretory
phenotypes (SASPs)
In addition to stable cell cycle arrest, senescent cells also
develop senescence-associated secretory phenotypes(SASPs), which contribute both positively and negatively tothe onset of inflammatory diseases such as cancer (depending on the biological context). Despite considerable progressin understanding the biological roles of SASPs, far less isknown about how they are induced.
Thus, a greater understanding of the underlying molecularmechanisms will lead to novel therapeutic strategies forvarious aging-associated diseases, including cancer.
Similar to aging, obesity is associated with cancer. However, the underlying mechanisms are not well understood.
Recently, we traced the association between obesity andincreased cancer risk to gut microbiota communities that
produce DNA-damaging bile acid. We found that DNA-damaging bile acid promotes development of obesity-associatedliver cancer by inducing SASPs in hepatic stellate cells. We
are now focusing on the potential clinical implications ofthese findings.

Assoc. Prof.：Sugiko Watanabe ／Asst. Prof.：Shimpei Kawamoto ／Postdoc.：Masahiro Wakita ／Postdoc.：Tatsuyuki Matsudaira ／Postdoc.：Megumi Narukawa ／Grad. Student 4

Eiji Hara
Professor
Dr. Hara received his Ph.D. from Tokyo University of Science in 1993. After working at Imperial
Cancer Research Fund Laboratories, U.K. (Postdoctoral Fellow), Cancer Research UK-Paterson
Institute, U.K. (Group Leader) and the Institutefor Genome Research, University of Tokushima(Professor), he was appointed Division Chief in
the Cancer Institute, Japanese Foundation forCancer Research in 2008. He took his current
position at RIMD from 2015.

Fig. 1.
Cellular senescence initially inhibits proliferation of damaged cells, thereby acting as a fail-safe
mechanism. However, in the long term, senescent cells may eventually promote tumorigenesis via SASPs.

Publication

20(1)Downregulation of cytoplasmic DNases
is implicated in cytoplasmic DNA
accumulation and SASP in senescentcells. Takahashi A., et al. Nat Commun.
(2018) 9(1):1249(3) DNA damage signaling triggers
degradation of histone
methyltransferases through APC/CCdh1
in senescent cells. Takahashi A., et al.
Molecular Cell (2012) 45:123-31.

(5) Mitogenic signalling and the p16INK4aRb pathway cooperate to enforce
irreversible cellular senescence.
Takahashi A., et al. Nature Cell Biology(2006) 8:1291-7.

(2) Obesity-induced gut microbial
metabolite promotes liver cancer
through senescence secretome.
Yoshimoto S., et al. Nature (2013)
499:97-101.

(4) Real-time in vivo imaging of p16Ink4a
reveals cross-talk with p53. YamakoshiK., et al. Journal of Cell Biology (2009)
186:393-407.

(6) Opposing effects of Ets and Id proteinson p16INK4a expression during cellularsenescence. Ohtani N., et al. Nature(2001) 409:1067-70.

6 weeks

12 months

20 months

Fig. 2.Real-time bioluminescence imaging of p16INK4a gene expression during aging(Journal of Cell Biology 186: 393-407. 2009).

21

Division of Cellular and Molecular Biology

Department of
Oncogene Research
Cancer develops due to accumulation of
mutations within a cell, which can then become
malignant through immortalization and transformation. The malignant traits of cancer cells occur
as they evade cancer inhibitory mechanisms suchas apoptosis and senescence and acquire capacity for autonomous proliferation. In addition, cancer
cells acquire invasive and metastatic characteristics through the loss of intercellular communication and altered cell morphology.

Staff
Assoc. Prof.：Shigeyuki Nada ／Assoc. Prof.：Norikazu Yabuta ／Asst. Prof.：Kentaro Kajiwara ／●Src and cancer development●The molecular mechanism underlying
p18/Ragulator and mTOR nutrient signaling

Src is a signaling molecule that localizes to the sub-membrane and was the first oncogene to be discovered. Normal
tissues retain morphology by maintaining contact between
neighboring cells via cell-cell junctions; however, cancer
cells exhibit altered morphology (shown in Fig. 1) and undergo invasion and metastasis by secreting growth factors
and proteases. Our laboratory has examined the role of Src
as an activator of signaling pathways that control remodelingof the cytoskeleton, which contributes to motility by inducing
morphological changes. In addition, Src is involved in cell
membrane-mediated signaling pathways that promote expression of genes encoding proteases, thereby leading tomalignancy. We aim to further elucidate the detailed molecular mechanisms by which Src affects cancer cell invasion
and metastasis.

mTOR is responsible for nutrition- and growth-related signaling in cells, and is involved in various biological phenomena. Our laboratory discovered that the p18 protein acts as
an adaptor for molecules involved in regulating mTOR, andthat it plays a crucial role in activating mTOR (Fig.1). We willcontinue our research into the molecular mechanism bywhich p18 regulates mTOR using protein structural analysis
and by studying the molecular interactions between otherfactors involved in mTOR regulation.
In addition, we are studying the molecular mechanisms underlying cancer defense in naked mole rats (NMR). NMR
are rodents that are similar to mice; however, they are uniquein that they have an exceptionally long life span (up to 10
times that of mice). They also exhibit significant resistanceto aging and cancer. Our laboratory focuses on identifying
the molecular mechanisms that allow NMR to acquire these
traits.

Interestingly, unlike other oncogenes, Src harbors no mutations. We found that Src is involved in a phenomenon
called “cell competition,” in which cells interact and competewith each other, producing a “winner” based on their relative
fitness. We anticipate that revealing the relationship between Src and cell competition will increase our understanding of the function of Src in cancer development; these studies are ongoing.

Postdoc.：Akira Ogawa ／Undergrad. Student 3 ／ Grad.
Student 10

Masato Okada
Fig. 1. Src activation induces morphological changes and increases cell mobility.

Professor
Dr. Okada graduated Kyoto University Schoolof Science in 1981 and received his Ph.D.
from Osaka University in 1988. He worked asa Research Associate at the Institute for Protein Research in Osaka University andbecame an Associate professor in 1996 in
the same institution. He was appointed current position as a Professor of RIMD in 2000.

Publication(1) Structural basis for the assembly of the
Ragulator-Rag GTPase complex. YoneharaR., et al. Nature Commun (2017) 8:1625(2) The Rho guanine nucleotide exchange
factor ARHGEF5 promotes tumor
malignancy via epithelial-mesenchymaltransition. Komiya Y., et al. Oncognesis(2016) 5: e25822(3) p18/LAMTOR1: a late endosome/lysosome-speciﬁc anchor protein forthe mTORC1/MAPK signaling pathway.
Nada S., et al. Methods Enzymol (2014)
535:249-63(4) The novel lipid raft adaptor p18
controls endosome dynamics byanchoring the MEK-ERK pathway tolate endosomes. Nada S., et al. EMBO
J. (2009) 28:477-89(5) The lipid raft-anchored adaptor protein
cbp controls the oncogenic potential ofc-Src. Oneyama C., et al. Mol Cell
(2008) 30:426-36(6) Transmembrane phosphoprotein Cbp
regulates the activities of Src-familytyrosine kinases. Kawabuchu M., et al.
Nature (2000) 404:999-1003

Fig. 2. Protein Structure for Ragulator complex

23

Division of Cellular and Molecular Biology

Department of
Signal Transduction
Tissue-specific stem cells continuously produce
terminally differentiated functional cells andmaintain organ integrity. Blood vessels supply
oxygen and nutrients to all tissues; tissues andorgans cannot develop without blood vessel
formation. Our aim is to elucidate the cellular andmolecular mechanisms underlying vascularformation (particularly those involving stem cells)
and to develop strategies to manage patients with
vascular diseases.

Staff
Assoc. Prof.：Hisamichi Naito ／Asst. Prof.：Hiroyasu Kidoya ／Postdoc.：Wei-Zhen Jia ／Postdoc.：Fumitaka Muramatsu ／Postdoc.：Yumiko Hayashi●Mechanism of vascular formation●Stemness and vascular niche

Tissue homeostasis in all organs is maintained via a highly
hierarchal architecture of blood vessels, which is precisely
regulated in an organ-specific manner. We are examining
how blood vessel diversity is regulated, focusing on theprocesses of angiogenesis and blood vessel maturation.
Our recent studies clarified that arterial-venous alignmentis regulated by the apelin/APJ system and is critical forthermoregulation (Kidoya, Dev Cell 2015).

Stem cells localize in perivascular areas in many organs.
Cells that comprise such a vascular niche regulate the“stemness” of stem cells. In our cancer stem cell (CSC)
model based on PSF1 promoter activity, we found that
CSCs proliferate and survive in the vascular niche (Nagahama, Cancer Res 2010, Kinugasa, Stem Cells 2014).
Regulation of the vascular niche is a promising approach toinhibiting tumor growth. Because blood vessels developingin the tumor microenvironment are immature and abnormal, normalization of blood vessel development must
control CSCs in the vascular niche. Vascular normalization
also improves anti-tumor immunity and drug delivery.
Therefore, we are seeking ways to normalize blood vessels
within tumors.

●Development of tissue regeneration methods based on endothelial stem cells
We have identified endothelial stem cells in pre-existingblood vessels and showed their utility for vascular regeneration (Naito, EMBO J 2012). Recently, we found that suchendothelial stem cells affect the resistance of cancer cells

E 14.5E 15.0to anti-angiogenic therapy (Naito, Cancer Res 2016). We
are examining how endothelial stem cells develop and how
they are maintained during development with a view tousing this cell population to treat vascular disease.

E 15.0Nobuyuki Takakura
Professor
Dr. Takakura obtained his Ph.D in Graduate
School of Medicine, Kyoto University in 1997.
He was appointed Professor of RIMD in 2006
after working at Kumamoto University as an
assistant professor for 4 years and Kanazawa
University as a professor for 5 years.

Fig. 1. Vascular development in mouse embryos. Hierarchal architecture of blood vessels accompanied by arterial (yellow)–venous(blue) alignment. Green; endothelial cells.

initiation

repaired

Publication(1) Regnase-1-mediated post-transcriptional
regulation is essential for hematopoietic
stem and progenitor cell homeostasis.
Kidoya H. et al., Nat Commun. (2019) 10(1):1072.
(2) TAK1 prevents endothelial apoptosis andmaintains vascular integrity. Naito H., etal., Dev Cell. (2019) 48(2):151-166.e7.

24(3) CD157 marks tissue-resident endothelial
stem cells with homeostatic andregenerative properties. Wakabayashi T.,
et al. Cell Stem Cell 22(3):384-397, 2018.
(4) APJ regulates parallel juxtapositionalalignment of arteries and veins in theskin. Kidoya H., et al. Dev Cell (2015) 33(3):247-59.

(5) A role for hematopoietic stem cells inpromoting angiogenesis. Takakura N.,
et al. Cell (2000) 102(2):199-209.
(6) Critical role of the TIE2 endothelial cell
receptor in the development of
deﬁnitive hematopoiesis. Takakura N.,
et al. Immunity (1998) 9(5):677-86.

Fig. 2. Endothelial cells (blue) andCSCs (green) in a tumor.
CSCs localize at the perivasculararea, the so called “vascular niche.”Fig3. Linage tracing of VESC. New blood vessels emerged from VESC (shown ingreen) Most of the endothelial cells (ECs) are replaced by ECs drived from VESC.

25

Division of Cellular and Molecular Biology

Department of
Cellular Regulation
Most cancers originate from epithelial cells. Normal
epithelial cells form a sheet-like tissue structure inwhich cells are tightly attached to each other and tothe basement membrane. Through malignant
progression, cells proliferate and expand by invading surrounding tissues. Furthermore, cells metastasize to distant organs via blood vessels, forming
often incurable tumors. Our aim is to elucidate themechanism underlying this mysterious process ofcancer development.

Staff●Role of PRL in malignant progression ofcancers●Functional analyses based on organoidculture of intestinal epithelia

PRL is highly expressed in malignant tumors and promotes
cancer metastasis. We discovered that PRL associates with
CNNM4, a Mg2+ transporter, and inhibits its Mg2+ transporting activity. Moreover, we also found that intestinal polyps
became malignant and invaded the surrounding muscle
tissue when CNNM4 was disrupted. At present, we areinvestigating the functional relationship between cancer
malignancy and Mg2+ dyshomeostasis caused by CNNM4
inhibition.
In normal epithelial tissues, cells are attached to each otherand collectively maintain their structure; these characteristics are disrupted in cancer tissues. Forced expression of
PRL in epithelial cells cultured on matrix gels induced amarked change in their morphology; some cells invaded
into the matrix only when PRL-expressing cells weresurrounded by non-expressing cells. These results suggestthat physical interaction between PRL-expressing cells andnon-expressing cells stimulates invasive behavior during
malignant progression. We are trying to clarify the molecular mechanism underlying this function of PRL.

A method of culturing intestinal epithelia in 3D matrix gelsthat mimic in vivo situations was recently developed; thesystem is called organoid culture. In this system, intestinal
epithelial cells differentiate and form a structure comprisinga monolayer sheet of cells. We are using this organoidculture system to investigate the role of PRL/CNNM in cellproliferation, differentiation, and cancerous transformation.
Many oncogenes and anti-oncogenes involved in regulating cell proliferation and survival have been identified. By
contrast, characteristics involved in transformation ofepithelial cells in a 3D space, which accompany architectural changes (such as invasion and metastasis) in tissues,
remain unclear. For example, how do cancer cells exit theepithelial tissue in which they are “born” and expand theirterritory by invading surrounding tissues? We are tacklingthese problems and trying to identify the mechanisms
underlying cancer development.

Assoc. Prof.：Daisuke Yamazaki ／Asst. Prof.：Yosuke Funato ／Postdoc.：Osamu Hashizume ／Grad. Student 8

Hiroaki Miki
Professor
Dr. Miki received his Ph.D from University ofTokyo in 1998. He was appointed Professor in
RIMD after working at the Institute of Medical
Science, Universuty of Tokyo and at the Institute for Protein Research, Osaka University.

Fig. 1. Macroscopic images of theintestine (left) and histological images of polyps (right) in the indicatedgenetically engineered mice. CNNM4-deficient mice develop adenocarcinomas that invade the muscle
layer (arrows).

Publication

26(1) Phosphocysteine in the PRL-CNNM
pathway mediates magnesium
homeostasis. Gulerez et al. EMBO Rep.
(2016) 17(12):1890-1900.

(3) Membrane protein CNNM4-dependent
Mg2+ efflux suppresses tumor
progression. Funato Y., et al. J Clin
Invest. (2014) 124(12):5398-5410.

(2) Mg2+ Extrusion from Intestinal Epitheliaby CNNM Proteins Is Essential for
Gonadogenesis via AMPK-TORC1
Signaling in Caenorhabditis elegans.
Ishii T., et al. PLoS Genet. (2016) 12(8):e1006276.

(4) Basolateral Mg2+ extrusion via CNNM4
mediates transcellular Mg2+ transport
across epithelia: a mouse model.
Yamazaki D., et al. PLoS Genet. (2013)9(12):e1003983.

(5) Thioredoxin mediates
oxidation-dependent phosphorylationof CRMP2 and growth cone collapse.
Morinaka A., et al. Sci Signal. (2011) 4(170):ra26.
(6) Nucleoredoxin sustains Wnt/β-cateninsignaling by retaining a pool of inactive
dishevelled protein. Funato Y., et al.
Curr Biol. (2010) 20(21):1945-52.

Fig. 2. Organoid culture of intestinal epithelia from the indicatedgenetically engineered mice.
CNNM4 deficiency causes morphological abnormalities.

27

●A new concept of tissue homeostasis“Morphostasis”●Aging program and its regulation

Developing animal tissues are reproducibly formed in thesame shape even in the presence of internal fluctuations
and external perturbations (developmental robustness).
Adult tissues also maintain a stable morphology while
replacing old or damaged cells with new healthy cells(tissue homeostasis), but its dysregulation is involved invarious diseases. We are focusing common groundbetween “developmental robustness” and “tissue homeostasis” and regard it as “Morphostasis”. Specifically, using azebrafish as a model animal which is suitable for in vivo
imaging analysis of cell-cell communication and tissue
dynamics and genetic analysis, we are exploring unknown
molecular systems supporting developmental robustness
and testing their potential roles in adult tissue homeostasis
and their dysregulation in disease. We try to combine developmental biology and disease study to establish a newconcept of tissue homeostasis.

We are tackling the exploration of the molecular mechanisms underlying individual aging. Aging mechanisms
have been studied using worm (C.elegans) and fly(Drosophila)as model animals because their life spans arevery short. However, their organs are quite different fromthose of human. In addition, the life spans of mouse andzebrafish, which are well used as human disease model,
are very long (3~4years). So, researchers have been
searching for short-lived vertebrates. Our lab is using ashort-lived fish “turquoise killifish” (the life span of which is
3~6months) as a new aging model. This fish shows
age-dependent decline of motility, fertility, and cognitive
function, similar to human. We are challenging the clarification of human aging mechanisms and the development of
new technique extending “healthy life expectancy”, using
turquoise killifish!

Genome Information Research Center

Department ofHomeostatic regulation
In our body, cells recognize its position and roles via
cell-cell communication and behave appropriately.
Such cell behavior supports tissue morphogenesis
and homeostasis, and its dysregulation is involvedin congenital malformation, cancer, degenerative
diseases, and aging. We focus especially on thecell-cell communication and behavior supporting
tissue homeostasis and explore unknown molecularsystems controlling embryonic development, organogenesis, regeneration, aging, and disease, using invivo imaging, model animal genetics, molecular andcell biology, and biochemistry.

Tohru Ishitani
Professor
Prof. Ishitani received his Ph.D. from Nagoya
University in 2002. After working as postdoctoral fellow in the same university, he became Associate Professor in the Medical Institute of Bioregulation, Kyushu University in 2006. He wasappointed Professor in the Institute for Molecular and Cellular Regulation, Gunma University
in 2017. He took his current position at RIMD in
2019. He received Young Scientists' Prize of The
Commendation for Science and Technology by
MEXT in 2009, and Samuro Kakiuchi Memorial
Award by the Japanese Biochemical Society in
2014.

Publication

28(1) Hipk2 and PP1c cooperate to maintain
Dvl protein levels required for Wnt
signal transduction. Shimizu N., et al.
Cell Reports (2014) 8(5) 1391-1404(3) NLK positively regulates Wnt/β-cateninsignalling by phosphorylating LEF1 inneural progenitor cells. Ota S., et al.
EMBO Journal (2012) 31:1904-15(2) Visualization and exploration of Tcf/Lef
function using a highly responsive
Wnt/β-catenin signaling-reportertransgenic zebraﬁsh. Shimizu N., et al.
Developmental biology (2012) 370(1)71-85(4) Nemo-like kinase suppresses Notch
signalling by interfering with formationof the Notch active transcriptional
complex. Ishitani T., et al. Nat. Cell Biol.
(2010) 12:278-85(5) Nrarp functions to modulate
neural-crest-cell differentiation by
regulating LEF1 protein stability.
Ishitani T., et al. Nat. Cell Biol. (2005)
7:1106-12(6) The TAK1-NLK-MAPK-related pathway
antagonizes signalling between
beta-catenin and transcription factor
TCF. Ishitani T., et al. Nature (1999)
399:798-802

29Genome Information Research Center

Department of Experimental
Genome Research
In the past, animals harboring natural mutations
have been used to elucidate the mechanisms
underlying various diseases. In the “post-genome
project era,” genetically modified animals play a keyrole in basic molecular biological investigations andact as models of human disease. Our laboratory
studies the mechanisms underlying mammalian
reproductive systems through genetic manipulationof animal models.

Staff
Asst. Prof.: Haruhiko Miyata / Asst. Prof.:
Taichi Noda / Asst. Prof.: Keisuke Shimada /SA Asst. Prof.: Daiji Kiyozumi (concur.) / SA
Asst. Prof.: Tsutomu Endo (concur.) / SA
Asst. Prof.: Julio Castaneda / Postdoc: Lu
Yonggang / JSPS Research Fellow:
Nobuyuki Sakurai / JSPS Research Fellow:
Yamauchi (Ishikawa) Yu / Guest Professor:●Analysis of molecular mechanisms involvedin mammalian gametogenesis, fertilization,and implantation●Development of new technologies for
producing genetically modified animals

We were the first laboratory in the world to produce genetically modified mice that express green fluorescent protein(GFP) throughout the body (Fig. 1). These green fluorescent mice are useful for many types of research projects.
Indeed, we used these animals to label sperm with fluorescent protein and visualize the fertilization process (ExpAnim. 2010; JCS. 2010, 2012; PNAS. 2012, 2013) (Fig. 2).
Recently, we found that calcineurin (PPP3CC/PPP3R2) isessential for sperm motility and male fertility (Science.
2015). Inhibiting sperm calcineurin may lead to the development of a reversible male contraceptive.

Another tool improved by work in our laboratory is lentiviral(LV) vector-mediated genetic manipulation in vivo. We developed the technique of placenta-specific gene manipulation
by transducing blastocyst stage embryos with LV vectors(Nat Biotechnol. 2007; PNAS. 2011). Using this technique,
we are trying to elucidate the mechanism underlying implantation and placentation.
We also established rat embryonic stem (ES) cells andgenerated mouse↔rat chimeric animals. We would like to
use this animal model to study body/organ size control in
vivo; indeed, this method may enable derivation of variousorgans from ES or iPS cells (Genes Cell. 2011; Sci Rep.
2016).
Our recent interest is using the CRISPR/Cas9 system togenerate genetically modified animals to study fertilization,
implantation, and placentation. We have had success inmice and rats using sgRNA/Cas9-expressing plasmids (Sci
Rep. 2013,2016; DGD. 2014; PNAS.2016; Nat. Commun.
2016).
Our laboratory and the Animal Resource Center for Infectious Diseases (http://www.arcid.biken.osaka-u.ac.jp/) offer
support services such as generation of genetically modified
animals, in vitro fertilization, and cryopreservation of mousestrains. For more information, please visit our homepage(http://www.egr.biken.osaka-u.ac.jp/index.php).

Martin M. Matzuk / Guest Associate
Professor: Yoshitaka Fujihara / Guest
Researcher: Masaru Okabe / Undergrad.
Student 1 / Grad. Student 10

Masahito Ikawa (concur.)Professor
Dr. Ikawa received his Ph.D. from Osaka University in 1997. After working as JSPS postdoctoral fellow and a Research Associate at Genome
Information Research Center in Osaka University, he spent 2 years at The Salk Institute in the
USA as a Research Associate. After returning
to Osaka University in 2002, he became an Associate Professor in 2004 and was appointed
to the current position in 2012. He was awarded
JSPS Prize in 2013. His lifework is to study
mammalian reproductive systems using genetically engineered mice.

Fig. 1. GFP-expressing mice are useful for many types of research project.
Genetically modified animals play a key role in basic molecular biology-based
investigations and are good models for studying human disease.

Publication(1) New Insights into the Molecular Eventsof Mammalian Fertilization. Satouh Y.,
e al. (2018) Trends Biochem Sci. 43(10):818-828(2) Sperm-borne phospholipase Czeta-1
ensures monospermic fertilization in
mice. Nozawa K., et. Al., (2018) Sci Rep.
8(1):1315.

30(3) TCTE1 is a conserved component of thedynein regulatory complex and isrequired for motility and metabolism inmouse spermatozoa. Castaneda J.M., etal., PNAS (2018) 114 (27):E5370-E5378(4) Structural and functional insights into
IZUMO1 recognition by JUNO inmammalian fertilization. Kato K., et al.
Nat Commun. (2016) 7:12198.

(5) Genome engineering uncovers 54
evolutionarily conserved andtestis-enriched genes that are notrequired for male fertility in mice.
Miyata H., et al. Proc Natl Acad Sci USA.
(2016) 113(28):7704-10.
(6) Sperm calcineurin inhibition prevents
mouse fertility with implications formale contraceptive. Miyata H., et al.
Science. (2015) 350(6259):442-5.

Fig. 2. Mouse eggs (left) and sperm (right) labeled with fluorescent proteins. These gametes are used tovisualize the fertilization process. (Figs from Exp. Anim. 59(1), 105-7, 2010)31

Genome Information Research Center

Department of
Genome Informatics
We use single cell sequencing along with computational methods to study problems that are difficult or
impossible to observe by experimental methods
alone. Some of the problems we work on include:
analysis of B and T cell receptor repertoires,protein-nucleotide
interactions
andmultiplesequence alignment of protein and nucleotide
sequences. These themes are described in moredetail below.

●Multiple sequence alignment●Sequencing B and T cell receptors

Multiple sequence alignment (MSA) is an important stepin many computational biology pipelines and MAFFT is
one of the most popular programs for building MSAs1.
Since the first release of MAFFT in 2002, we have been
continuously improving its accuracy, speed and utility inpractical situations, and have provided different options
for newly emerging types of data and analyses. Recent
features include: inclusion of secondary structural
information of non-coding RNAs and proteins, interactive
selection of sequences for phylogenetic tree inference,and integration of protein sequences with comprehensive
structural alignments2. The latter feature plays a central
role in structural modeling methods in our lab.

A healthy immune system maintains a vast repertoire of B
and T cells that can recognize a wide range of molecules. B
and T cell receptors are produced by the combination of two
highly variable polypeptide chains which are encoded bydifferent mRNA transcripts. Due to the high variability of eachpolypeptide and the combination of two different molecules,
each individual’s repertoire of receptors is in general unique.
Several immunological and molecular methodologies havebeen employed to study the immune repertoire with a rather
low-resolution. Nevertheless, the advent of next generation
sequencing (NGS) has allowed to analyze millions of immune
receptor sequences in one sample (bulk sequencing). Thishas been of great value to the study of immune repertoires,but cannot reveal the pairing of receptor sequences. In thepast few years, single cell sequencing technologies haveemerged and have made it possible to study paired polypeptide chains from thousands of individual B and T cells. We are
currently making use of both bulk and single cell sequencing
techniques to study immune cell repertoires in health anddisease.

●Protein-nucleotide interactions●Analysis of B and T cell receptor specificity
and repertoires

Protein-nucleotide interactions play a central role in theflow of biological information in all living systems. In the
immune system, the importance of DNA-binding proteins in
the regulation of transcription has been studied extensively.
More recently, the importance of RNA-binding proteins(RBPs) in maintenance of homeostasis as well as in shaping the strength and duration of immune responses
post-transcriptionally has been noted6. In order to gain
further insight into the mechanisms of RBP-mediatedimmune regulation, we are developing tools for nucleotide
binding site prediction and flexible protein-nucleotide
docking which have been validated in a number of experimental studies.

Prediction of B and T cell receptor antigen specificities
from sequence is currently an important and open problem.
Our lab is approaching this challenge using a combinationof B and T cell receptor sequencing, structural modelingand artificial intelligence. We have developed a tool for
generating BCR and TCR 3D models in a high-throughput
and accurate manner 3. We have further extended thistechnology to cluster such models according to theirantigen and epitope specificity 4. We have also developed atool to build TCR-epitope-MHC structural models fromsequence5 and are working on new BCR epitope prediction
methods that make use of structural information. The
immediate goals of this research are to identify antigens
and epitopes that are associated with specific diseases
along with the B or T cell receptors that recognize theseantigens and epitopes.

Staff
Assoc. Prof. : Kazutaka Katoh ／Assoc. Prof.：Shunsuke Teraguchi(concur.）／
Asst. Prof.：Songling Li ／Asst. Prof.: Floris J.Van Eerden ／Postdoc : John Rozewicki ／Postdoc：Jan Wilamowski

Daron M. Standley
Professor
Prof. Standley received his PhD in Chemistry from
Columbia University in 1998. He then joined Schrodinger, Inc. where he worked as a scientific softwaredeveloper for five years. In 2003 he moved to the Institute for Protein Research, Osaka University as a
Senior Scientist. He joined the Immunology Frontier
Research Institute (IFReC) as a Principal Investigatorin 2008 and, after a two-year cross-appointment at
Kyoto University’s Institute for Virus Research,
became a Professor full time at the Research Institute for Microbial Diseases in 2016.

Publication

32(1) MAFFT multiple sequence alignment
software version 7: improvements inperformance and usability. Katoh, K., etal. Mol Biol Evol (2013) 30(4) 772-80(3) Repertoire Builder: High-throughput
structural modeling of B and T cell
receptors. Schritt, D., et al. (in prep)
https://sysimm.org/rep_builder/(2) Integrated sequence and structuralalignment using MAFFT and DASH.
Rozewicki, J., et al. (in prep)
https://sysimm.org/dash/(4) Functional clustering of B cell
receptors using sequence andstructural features. Xu, Z., et al. (inprep) https://sysimm.org/interclone/(5) Structural modeling of lymphocyte
receptors and their antigens. Li, S., etal. Methods Mol Biol (2019) In press(6) Regnase-1 and Roquin Regulate a
Common Element in Inflammatory
mRNAs by Spatiotemporally Distinct
Mechanisms. Mino, T., et al. Cell
(2015)161, 1058-1073

33

Genome Information Research Center

Department of
Infection Metagenomics
Next-generation sequencing (NGS) is a technology that can generate an enormous amount ofgenomic information in a short time and has
allowed huge progress in genomic science andinfectious disease research. Staffs at the Department of Infection Metagenomics who specialized
in bioinformatics, microbiology, and infectious
diseases gather to conduct research on pathogens and infectious diseases using NGS-based
genomic/metagenomic analysis.

Staff●Development of methods for pathogen
detection based on metagenomic analysis●Study of gut flora during onset of
infectious disease

A metagenome is the sum of all genomes of all organisms
inhabiting a particular environment. The emergence of NGS
has enabled comprehensive analysis of genomic information from large numbers of organisms, thereby leading tosignificant advances in metagenomic analysis. For example, comprehensive analysis of microbial genomes in bloodor nasopharyngeal samples from patients suffering from
diseases of unknown cause makes it possible to identify thepathogens causing these symptoms and the genetic factors
responsible for pathogenesis. This method, unlike conventional pathogen-specific methods, is applicable to various
types of sample (e.g., blood, nasal swab, stool). It can also
detect multiple pathogens in a single sample. Our laboratory uses metagenomic analysis to develop new methods forthe diagnosis of infectious diseases.

It is becoming clear that the gut flora is microbiota that is
involved in various diseases and plays an important role inhost defense. By performing metagenomic analysis ofchanges in and recovery of bacterial gut flora over time incases of diarrhea, our laboratory is studying the relationshipbetween human gut flora and pathogens. Furthermore, notonly is bacterial gut flora related to disease, but it is also
closely related to lifestyle factors. Our research is focusedon how bacterial gut flora is affected by environmental
factors and the physiological state of the individual.
NGS technology had made remarkable progress. New
hardware platforms are being developed. NGS itself reads
only nucleic acid sequences, and further analysis isrequired to handle the enormous amount of data obtained.
It is important to have a broad knowledge of bioinformatics,
microbiology, and genomics in order to select the appropriate model based on the characteristics of each sequencing
platform. At our laboratory, we carry out co-operative
research with specialists in the fields of bioinformatics,
microbiology, and infectious diseases.

●Genomic analysis of microbial pathogens

Assoc. Prof.：Naohisa Goto (concur.) ／SA Assoc. Prof.：Shota Nakamura (concur.) ／SA Asst. Prof.：Daisuke Motooka (concur.) ／Postdoc.：Yuki Matsumoto ／Postdoc.：Hiroya Oki

HiSeq3000

The molecular mechanisms underlying the pathogenicity ofmany infectious diseases remain unclear. Our laboratory
conducts genomic analysis-based research to identify genes
responsible for pathogenicity and to identify the molecularmechanisms by which infectious diseases develop.

MinION

Tetsuya Iida (concur.)Professor

HiSeq2500

MiSeq

Fig. 1.Large scale computer
system for NGS data analysis.

Fig. 2.

Publication(1) Non-Ischemic Heart Failure With
Reduced Ejection Fraction Is AssociatedWith Altered Intestinal Microbiota.
Katsimichas T. et al., N Circ J. (2018) Mar
30. doi: 10.1253/circj.CJ-17-1285.
(2) A case of severe soft tissue infection
due to Streptococcus tigurinus
diagnosed by necropsy in which
genomic analysis was useful forclarifying its pathogenicity. Yoshizawa
H., et al., Pathol Int. (2018) doi:
10.1111/pin.12656.
34(3) Fungal ITS1 Deep-Sequencing Strategies
to Reconstruct the Composition of a
26-Species Community and Evaluationof the Gut Mycobiota of Healthy
Japanese Individuals. Motooka D., et al.,Front Microbiol. (2017) 8:238.
(4) The cell envelope-associatedphospholipid-binding protein LmeA is
required for mannan polymerization in
mycobacteria. Rahlwes K.C., et al., J
Biol Chem. (2017) 292(42):17407-17417.

(5) The clinical and phylogenetic
investigation for a nosocomial
outbreak of respiratory syncytial virus
infection in an adult hemato-oncology
unit. Nabeya D., et al., J Med Virol.
(2017) 89(8):1364-1372.

Genomic analysis of Vibrio parahaemolyticus using four models of next-generation
sequencer: ■454 GS Jr（Roche）、■IonPGM（Life Technologies）、■MiSeq（Illumina）、■Pacific Biosciences RS System (PacBio)
GS Jr, MiSeq, and IonPGM produce short reads. Therefore, they require assembly of
short fragments. The third generation sequencer, PacBio, on the other hand can produce
long reads and assemble them into two long sequences with lengths equivalent to two
chromosomes. However, PacBio has low accuracy with respect to sequence information.
Although the read length of MiSeq is far shorter than that of PacBio, it has a much higher
yield. Thus, to conduct a proper analysis it is necessary to understand the characteristics
of each sequencing platform.

35

Genome Information Research Center
Genome Information Research Center

Next-Generation Sequencing (NGS)Core Facility

Staff
Prof. (concur.) : Tetsuya Iida, Ph.D.
SA Assoc. Prof. (concur.) : Shota
Nakamura, Ph.D.
Asst. Prof. : Daisuke Okuzaki, Ph.D.
SA Asst. Prof. (concur.) : Daisuke
Motooka, Ph.D.

To prevent and control infectious diseases, it is essential tounderstand both the mechanisms of pathogenicity as well as
host immune responses. The NGS Core Facility of the
Genome Information Research Center was founded tosupport and provide genomic technologies for research on
infectious diseases and immunology. We are supporting
researchers in analyzing large volumes of data obtained from
NGS by combining bioinformatics approaches with large
computing systems designed for big data. Recently, we havebegun supporting activities outside of infectious diseaseresearch for researchers from Osaka University as well asother universities.
In the last decade, as a result of the remarkable technologicalinnovation of NGS systems, which can read a massive
number of sequences simultaneously and at high speed, weare now able to analyze genomic information quickly and at
low cost. Various NGS instruments including MiSeq, HiSeq(Illumina), and MinION (Oxford Nanopore) are available in ourCore Facility. We provide genomics applications according toresearchers’ needs in addition to training courses covering
topics such as NGS procedures as well as other related
experimental technologies. Furthermore, we are expanding
research with the aim of improving bioinformatics analysis incollaboration with the Department of Genome Informatics andthe Department of Infection Metagenomics.

Laboratory of
Genome Research
We are currently using animal models to investigate
the molecular biological mechanisms involved inhuman disease, particularly cardiovascular disease.

Takeshi Miwa
Associate Professor
Dr.Takeshi Miwa received his Ph.D. from Osaka
University in 1983. He appointed as a Assoc.
prof. in RIMD after working at The University ofTokyo and Stanford University.

Publication(1) Connexin45 contributes to global cardiovasculardevelopment by establishing myocardial impulse
propagation. Nishii K., et al. Mech Dev. (2016) 140:41-52(3) Interleukin-16 promotes cardiac ﬁbrosis and myocardial
stiffening in heart failure with preserved ejection fraction.
Tamaki S., et al. PLoS One (2013) 8(7):e68893(2) A novel heart failure mice model of hypertensive heartdisease by angiotensinⅡ infusion, nephrectomy, and saltloading. Tsukamoto Y., et al. Am J Physiol Heart Circ Physiol.
(2013) 305:1658-67(4) L-Carnitine prevents the development of ventricular ﬁbrosis
and heart failure with preserved ejection fraction in
hypertensive heart disease，Omori Y., et al. J Hypertens.
(2012) 30:1834-44

Next Generation Sequencer HiSeq

Publication(1) Clinical implications of monitoring nivolumab immunokinetics in
non-small cell lung cancer patients. Osa A., et al. JCI Insight (2018)
Oct 4;3(19).
(2) Heme ameliorates dextran sodium sulfate-induced colitis throughproviding intestinal macrophages with noninflammatory proﬁles.
Kayama H., et al., Proc Natl Acad Sci U S A. (2018) Aug 14;115(33):8418-8423.
(3) Semaphorin 6D reverse signaling controls macrophage lipid
metabolism and anti-inflammatory polarization. Kang S., et al. Nat
Immunol. (2018) Jun;19(6):561-570.

Large-scale computer system for NGS(4) Phenotype-genotype correlations of PIGO deﬁciency with variablephenotypes from infantile lethality to mild learning difﬁculties.
Tanigawa J., et al. Hum Mutat. (2017) Mar 23. 38;7::805-815.

1) We have established a diastolic heart failure model using Dahl salt-sensitive rats. This model showed that left ventricular (LV) fibrosis and stiffening play crucial roles in the development of heart failure with preserved
ejection fraction (HFpEF). Digitalis-like factors and the subsequent activation of the Na+/Ca2+ exchanger may play important roles in the development of hypertensive HFpEF and also regulate the effect of carnitine whenadministered to the HFpEF model. In addition, serum interleukin-16 (IL-16)
levels are elevated both in patients with HFpEF and in the rat model.
Increased cardiac expression of IL-16 in transgenic mice induces cardiac
fibrosis and LV myocardial stiffening, which is accompanied by increased
macrophage infiltration (Fig. 1).
2) To understand the cellular and molecular aspects of vascular smoothmuscle (SM) cell growth in atherosclerotic plaques, we characterized themechanisms responsible for transcription of SM-specific genes, particularly
the human SM alpha-actin (SmαA) gene (Fig. 2). Several cis-acting DNA
elements and transcriptional nuclear factors essential for SmαA expression
have been identified. Since SmαA is also expressed in many tissues during
acute inflammation, we are examining expression of the SmαA and its
function(s).

Fig. 1. Increased cardiac expression of IL-16 in mice undercontrol of the α-MHC promoter causes increased myocardial
fibrosis and stiffness. (Left) Four-chamber view of hearts from
non-transgenic and transgenic mice. (Right) Sirius Red-stained
sections of the LV from fibrotic areas.

Fig. 2. Embryonic aorta (Ao) express the human vascular SM
α-actin promoter (left), but those with -1M (center) and 4M(right) point mutations in the transcriptional nuclear factor-binding regions do not.
36

37Research Center for Infectious Disease Control

Department ofBacterial Infections
In our laboratory, we are conducting research andcollecting genomic information to understand how
bacterial pathogens infect the host and cause
disease. In addition, by developing new pathogen
detection methods using high-throughput DNA
sequencers, we aim to identify novel pathogens andreveal the pathogenesis of unknown infectious
diseases.

Staff
Assoc. Prof.：Toshio Kodama ／Asst. Prof.：Shigeaki Matsuda ／●Identifying the mechanism(s) underlying
bacterial infection and pathogenesis●Development of methods to diagnosebacterial infections based on genomics
and metagenomics

We performed whole genome sequencing of Vibrio parahaemolyticus, a bacterium that causes acute gastroenteritis in humans, and revealed that the type III secretion
system T3SS2 is essential for pathogenicity. T3SS2 directly injects bacterial proteins (effectors) into target host cells.
We demonstrated that injection of those effectors by
T3SS2 from V. parahaemolyticus leads to inflammation of
the intestinal mucosa and diarrhea. Currently, we are analyzing the molecular mechanism by which those effectors
cause the symptoms of acute gastroenteritis.
Also, we revealed that expression of the genes encoding
T3SS2 is induced by bile. In fact, chemical substances that
adsorb and remove bile suppressed symptoms caused by
V. parahaemolyticus in animal models, suggesting thatthese substances may be new therapeutic agents for V.
parahaemolyticus infection. This is an example of “anti-virulence therapy” rather than antimicrobial therapy. This kindof approach is expected to provide novel therapeutic strategies for various bacterial infections.
Furthermore, based on findings obtained from our researchon pathogenicity, we aim to explore the life cycle of bacterial
pathogens in their natural environments.

Emerging and re-emerging infectious diseases cause
many problems worldwide. In many cases of such
infection, the causative agent is unknown and/or the pathogenic mechanism is not yet clear. To identify the agentsthat cause such infections, and to understand the underlying pathogenesis, we are developing a high-throughput DNA
sequencing-based system to detect pathogens andanalyze their virulence traits.

SA Asst. Prof.：Pranee Somboonthum／ Undergrad. Student 1 ／Grad. Student 3

Tetsuya Iida
Professor
Dr. Iida graduated Faculty of Science, Kyoto
University in 1984 and received his Ph.D. from
Osaka university in 1991. He was appointed
SA Professor at the International ResearchCenter for Infectious Diseases in RIMD afterworking as a Research Associate for six years
and an Associate Professor for seven years.
He took his current position as a Professor of
RIMD in 2015.

Fig. 1. The genomes of bacteria belonging to genus Vibrio
comprise two distinct circularchromosomes.（Lancet, 2003）

Publication(1) Export of a Vibrio parahaemolyticus
toxin by the Sec and type III secretion
machineries in tandem. Matsuda S. etal., Nat. Microbiol (2019) doi:
10.1038/s41564-019-0368-y. in press(2) A repeat unit of Vibrio diarrheal T3S
effector subverts cytoskeletal actin
homeostasis via binding to interstrand
region of actin ﬁlaments. Nishimura M.,
et al. Sci Rep. (2015) 5:10870.

38(3) Interaction between the type III effector
VopO and GEF-H1 activates the
RhoA-ROCK pathway. Hiyoshi H., et al.
PLoS Pathog. (2015) 11(3):e1004694.
(4) A cytotoxic type III secretion effector of
Vibrio parahaemolyticus targets vacuolar
H+-ATPase subunit c and ruptures hostcell lysosomes. Matsuda S., et al. PLoS
Pathog. (2012);8(7):e1002803.

(5) VopV, an F-actin-binding type III secretion
effector, is required for Vibrio
parahaemolyticus-induced enterotoxicity.
Hiyoshi H., et al. Cell Host Microbe. (2011) 10(4):401-9. doi: 10.1016/j.chom.2011.08.014.
(6) Metagenomic diagnosis of bacterial
infections. Nakamura S., et al. Emerg
Infect Dis. (2008) 14(11):1784-6.

Fig. 2. Bile in the small intestine induces expression ofgenes encoding T3SS2, whichis the major virulence factor
produced by Vibrio parahaemolyticus, the causative agentof diarrhea.

39International Research Center for
Infectious Diseases

Research Center for
Infectious Disease Control

Laboratory of Clinical Researchon Infectious Diseases

Department of
Virology
Staff

Staff

Assis. Prof.：Yuta Kanai ／Grad. Student 1

Postdoc.：Takahiro Kawagishi ／Grad. Student 2

Takeshi Kobayashi
Associate Professor
Dr. Kobayashi received his Ph.D. from Osaka University in 2000. He became a Research associate
at RIMD in the same year. He spent for five years
as a postdoctoral fellow in Vanderbilt University,
USA before returning to Japan to work at the Institute for Virus Research in Kyoto University. He wasappointed SA Associate Professor of RIMD in2012. He is in his current position from 2016.

Publication(1) Development of stable rotavirus reporter expression
systems. Kanai Y., et al. (2019) J. Virol. 93:e01774-18(2) Lethal murine infection model for human respiratory
disease-associated Pteropine orthoreovirus. Kanai Y., et al.,
Virology (2018) 514:57-65.

SA Associate Professor
Dr. Kamitani received his Ph.D. from Osaka University in 2003. After working at RIMD for one year, hespent the period from 2004 to 2009 as a postdoctoral fellow at the University of Texas Medical Branch at
Galveston. He returned to the RIMD and became an
Associate professor for Global COE program. He
took his current position in 2013.

Publication(3) Entirely plasmid-based reverse genetics system forrotaviruses. Kanai Y., et al. (2017) Proc Natl Acad Sci U S A.
114:2349-2354.
(4) Reverse genetics for fusogenic bat-borne orthoreovirus
associated with acute respiratory tract Infections in humans:role of outer capsid protein sigmaC in viral replication andpathogenesis. Kawagishi T., et al. PLoS Pathog. (2016)
12:e1005455.

1) Rotaviruses (RVs)
RVs are highly important pathogens that cause severe
diarrhea in infants and young children worldwide. Understanding of the molecular mechanisms underlying the replication andpathogenesis of RVs has been hampered by the lack of areverse genetics system that allows the synthesis of recombinant viruses from artificial genes. Recently, we developed along-awaited plasmid-based reverse genetics system for RVs.
This technique opens up new horizons for studying the replication and pathogenesis of RVs. We are investigating RV biology
and developing vaccines and therapeutics using a combinationof genetic, biochemical, and biophysical approaches.
2) Oncolytic viral therapy using reoviruses
Mammalian orthoreoviruses (reoviruses) are members of thefamily Reoviridae and have a genome containing 10 segmentsof double-stranded (ds) RNA. Reoviruses are highly tractable
experimental models for studying the replication and pathogenesis of dsRNA viruses. In the last decade, reoviruses have been
evaluated as oncolytic agents against a variety of tumors,
including head and neck, colon, breast, and pancreatic cancers,in animal models and humans. This is based on the observationthat reoviruses induce cell death and apoptosis in tumor cells
40

Wataru Kamitaniwith an activated Ras signaling pathway. Wild-type
reovirus-based oncolytic therapies are safe, but their efficacy iscurrently limited. We are developing safer and more effective
reovirus-based cancer therapeutics by genetic modification.
3) Highly pathogenic bat-borne reovirus
Nelson Bay reovirus (NBV) was isolated from a flying fox in1968 but had not been associated with any disease. However,
NBVs were recently isolated from human patients sufferingfrom acute respiratory tract infections in Malaysia, Indonesia,
China, and Japan. These isolates have given rise to increasing concerns about bat-transmitted reovirus infections inhumans. We are investigating how NBV replicates andcauses disease in vitro and in vivo.

Fig. Generation of RVs from Cloned cDNAs(1) Middle East Respiratory Syndrome Coronavirus Spike
Protein Is Not Activated Directly by Cellular Furin during Viral
Entry into Target Cells. Matsuyama S., et al. J. Virol. (2018)
92(19). pii: e00683-18(2) MERS coronavirus nsp1 participates in an efﬁcient
propagation through a speciﬁc interaction with viral RNA.
Terada Y., et al. Virology. (2017) 511:95-105.

Coronaviruses infect many different animals, including
human, and cause them to have respiratory and gastrointestinal diseases. Newly emerged Middle East respiratory
syndrome coronavirus (MERS-CoV) and severe acute respiratory
syndrome coronavirus (SARS-CoV) infect respiratory tract
and cause severe pneumonia disease. Our research groupfocuses on these coronaviruses and studies the molecularbiology and host cell-virus interaction of these coronaviruses.
SARS-CoV is the etiological agent of a newly-emerged
human respiratory disease that originated in southern China
in 2002 and spread worldwide in the 2003 epidemic. After 10
years of the epidemic of SARS-CoV, novel coronavirus,
MERS-CoV, has been reported in Middle East region.
MERS-CoV spreads to North America, Europe, China, andKorea. No effective treatment against MERS-CoV. Our
research group studies about non-structural protein 1 (nsp1),
that is one of pathogenicity factor in Coronavirus. Nsp1 of
SARS-CoV induces host protein synthesis suppression
through binding to 40S ribosome complex. The nsp1
enhance viral replication through binding to viral RNA. Our
research group utilizes a Bacterial Artificial chromosome(BAC)-based revers genetics system for these coronavirus-(3) Two-amino acids change in the nsp4 of SARS coronavirus
abolishes viral replication. Sakai Y., et al. Virology. (2017)
510:165-174.
(4) Severe Acute Respiratory Syndrome Coronavirus nsp1
Facilitates Efﬁcient Propagation in Cells through a Speciﬁc
Translational Shutoff of Host mRNA. Tanaka T., et al. J. Virol.
(2012) 86(20):11128-37

es. Our group try to understand the mechanism of Coronaviruses replication and pathogenesis for development therapeutic targets against Coronaviruses using the BAC-based
revers genetics system.

Fig. Gene expression control by SARS-CoV nsp1
①Nsp1 binds to 40S ribosome, and then induces translational shutoff.
The nsp1-40S binding induces cleavage of mRNA.
②Nsp1 binds to viral mRNA, and then the interaction enhances viral
replication.

41

International Research Center for
Infectious Diseases

International Research Center for
Infectious Diseases

Laboratory of
Emerging Viral Diseases
Mammarenaviruses include highly pathogenic agents such
as Lassa (West Africa) and Junin (South America) viruses,
which cause viral hemorrhagic fever in humans and poseimportant public health problems within their regions ofendemicity. In addition, the worldwide-distributed, prototypic
mammarenavirus, lymphocytic choriomeningitis virus(LCMV) is a neglected human pathogen of clinical significance. Despite their substantial impact on human health,current therapeutic options for mammarenaviruses are very
limited. Our research focuses on investigating the molecularand cellular biology of mammarenaviruses to facilitate thedevelopment of novel antivirals and vaccines.

Masaharu Iwasaki
SA Associate Professor

Pathogenic Microbes
Repository Unit
The facility is part of the National BioResource Project(NBRP) directed by the Ministry of Education, Culture, Sports,
Science and Technology, Japan, and is a member of theJapan Society for Culture Collections (JSCC); therefore, wecollect and preserve pathogenic bacterial strains. Thesestrains are distributed to investigators in and outside thiscountry upon request. Our collection is listed on the website
for this facility (http://rceid.biken.osaka-u.ac.jp) and that of the
NBRP.

Staff
Head (concur.): Tetsuya Iida, Ph.D.
Associate Professor (concur.): Toshio
Kodama, Ph.D.

Collection list:
http://rceid.biken.osaka-u.ac.jp

Dr. Masaharu Iwasaki received his Ph.D. from Kyushu
University for his work on measles virus RNA synthesis and virion assembly in 2010 and graduated from
Kyushu University School of Medicine (MD-PhD program) in 2012. Thereafter, he worked as a Research
Associate (2012), a Senior Research Associate (2015),
and a Staff Scientist (2017) at The Scripps ResearchInstitute, where he studied the molecular mechanisms
underlying mammarenavirus multiplication. He wasappointed to his current position in 2018.

Publication(1) Interactome analysis of the lymphocytic choriomeningitis
virus nucleoprotein in infected cells reveals ATPase Na+/K+
transporting subunit Alpha 1 and prohibitin as host-cell
factors involved in the life cycle of mammarenaviruses.
Iwasaki M. et al., PLoS Pathog. (2018) 20;14(2):e1006892.
(2) The High Degree of Sequence Plasticity of the Arenavirus
Noncoding Intergenic Region (IGR) Enables the Use of aNonviral Universal Synthetic IGR To Attenuate Arenaviruses.
Iwasaki M. et al., J Virol. (2016) 90(6):3187-97.

42

Mammarenaviruses are simple enveloped viruses with abi-segmented ambisense RNA genome encoding four genes(Figure A). Each RNA segment, small (S) and large (L),directs the synthesis of two viral proteins from two open
reading frames, which are separated by a non-codingintergenic region (IGR). Despite this simple genome organization, we know very little about the mechanisms by whichthese viruses multiply and cause disease in infected hosts. To
better understand the complex biology of mammarenaviruses
and to develop antiviral strategies that can combat theseviruses, we use reverse genetics systems to generate recombinant mammarenaviruses, which contain pre-determinedmutations and/or additional foreign genes such as enhanced
green fluorescent protein (eGFP), from cloned cDNAs. We
used these technologies to generate a recombinant LCMV
harboring a synthetic LCMV S-IGR-like IGR instead of the
L-IGR [rLCMV(IGR/S-Ssyn)] (Figure B). rLCMV(IGR/S-Ssyn)
was severely attenuated in vivo but elicited protective immunity against a lethal challenge with wild-type LCMV. This strate-(3) General Molecular Strategy for Development of Arenavirus
Live-Attenuated Vaccines. Iwasaki M. et al., J Virol. (2015) 89(23):12166-77.
(4) Sodium Hydrogen Exchangers Contribute to Arenavirus Cell
Entry. Iwasaki M. et al., J Virol. (2014) 88(1):643-54.

gy can be used to generate live-attenuated vaccines for currently
known and potentially newly emerging hemorrhagic fever-causing
mammarenaviruses without the need to incorporate amino acidchanges. In addition, we generated recombinant LCMVs expressing
eGFP or an affinity-tagged viral protein to facilitate genetic andpharmacological screenings and proteomic analyses with the aim ofidentifying virus-host interactions required for efficient multiplicationof mammarenaviruses that can be exploited as druggable targets.

F i g . ( A ) S c h e m a t i c d i a g r a m o f t h e g e n o m e o r g a n i z a ti o n o fmammarenaviruses. (B) Predicted RNA secondary structures of the
LCMV S-IGR (left) and the synthetic LCMV S-IGR-like IGR (right).

43

Research Center for
Mechanism and Regulationof Aging

Germ Cell GroupThe life expectancy of humans has increased markedly overrecent decades. Ironically, this has resulted in a startling rise in
the incidence of aging-associated diseases, resulting in serious
social problems such as increased medical expenses andnursing care costs. To solve these problems, the ResearchCenter for Mechanism and Regulation of Aging was establishedin 2017. The center aims to clarify the fundamental mechanismsthat regulate aging and to understand the role of cellular senescence in aging and aging-associated diseases.

Staff
Director : Eiji Hara

Masami Nozaki
Associate Professor
Dr.Nozaki received his Ph.D. from Osaka University in 1986. He took his current position at
RIMD in 2007 after working as a Research
Associate and an Associate Professor in thesame institution.

Publication■ Division of Aging Model Organism
Department ofAging Rate Biology
Department of Research of
Signals Regulating Aging
Department of
Genetics and Metabolism
Department of
Cell-cell Communication
Department ofOrganismal Aging Research
Department ofAutophagy and Aging

Head: Invited Professor Eisuke Nishida
RIKEN Center for Biosystems Dynamics Research

Department of
Reproductive Aging
Department of AnimalLongevity and Aging
Research

44

Department of
Cell Senescence Mechanism

Head: Invited Professor Naoki Hisamoto
Group of Signaling Mechanisms,
Graduate School of Science, Nagoya University

Department of Aging-associatedStress Signaling

Head: Invited Professor Masayuki Miura
Dept. of Genetics, Graduate School of
Pharmaceutical Sciences, University of Tokyo

Head: Invited Professor Tatsushi Igaki
Lab of Genetics, Graduate School of Biostudies,
Kyoto University

Head: Cocurrent Professor Tohru Ishitani
Dept. of Homeostatic regulation, Research Institutefor Mcrobial Diseases, Osaka University

Head: Concurrent Professor
Tamotsu Yoshimori
Lab of Intracellular Membrane Dynamics, Graduate
School of Frontier Biosciences, Osaka University

Department ofSleep and Aging Regulation■ Division of Cellular Senescence

Head: Invited Researcher Akiko Sato
National Center for Geriatrics and Gerontology

Head: Concurrent Professor Masahito Ikawa
Dept. of Experimental Research, Research Institutefor Microbial Diseases, Osaka University

Head: Invited Associate Professor Kyoko Miura
Laboratory for Molecular Biology of Aging and Longevity,
Faculty of Life Sciences, Kumamoto University

Department of Senescent
Cell Morphology & Motility
Department ofSenescence Regulation
Department of TransposonMediated Processes
Department ofSenescent Metabolism
Department of
Immune Aging
Department of Brain Aging(1) LATS1/2 kinases trigger self-renewal of cancer stem cells in
aggressive oral cancer. Nozaki M. et al. Oncotarget (2019) 10(10): 1014-30.

(3) Interaction between basigin and monocarboxylatetransporter 2 in the mouse testes and spermatozoa. ChenC., et al. Asian J Androl (2016) 18 (4):600-6.

(2) Migration of oral squamous cell carcinoma cells are inducedby HGF/c-Met signalling via lamellipodia and ﬁlopodia
formation. Yasui H. et al. Oncol Rep (2017) 37 (6): 3674-80(4) Isolation and propagation of neural crest stem cells frommouse embryonic stem cells via cranial neurospheres.
Minamino Y., et al. Stem Cells Dev (2015) 24 (2):172-81.

Head: Concurrent Professor Eiji Hara
Dept. of Molecular Microbiology, ResearchInstitute for Microbial Diseases, Osaka University

Head: Invited Professor Hidenori Ichijo
Lab of Cell Signaling, Graduate School of
Pharmaceutical Sciences, The University of Tokyo

Head: Invited Professor: Yasuhiro Minami
Dept. of Physiology and Cell Biology,
Graduate School of Medicine, Kobe University

Head: Invited Professor Nakanishi Makoto
Div. of Cancer Cell Biology, The Insitute ofMedical Science, The University of Tokyo

Head: Invited Professor Haruhiko Shiomi
Dept. of Molecular Biology,
Keio University School of Medicine

Head: Invited Researcher Tomonori Kimura
KAGAMI Project, National Institutes ofBiomedical Innovation, Health and Nutrition

Head: Invited Professor Yoko Hamazaki
Dept. of Life Science Frontiers, Center for iPS Cell
Research and Application, Kyoto University

Head: Invited Researcher Kiyohito MizutaniDiv. of Pathogenic Signaling, Graduate School of
Medicine, Kobe University

Our body is derived from a single fertilized egg. During development, germ cells (and sometimes cancer cells), as well as many
types of tissues, are generated. We in the germ cell group havebeen conducting research focusing on germ cells, the early
embryo, stem cells, and cancer cells. Currently, we study osteogenesis from pluripotent stem cells and are characterizing cancer
stem cells.
Neural crest cells are derived from neuroepithelium via epithelial-mesenchymal transition (EMT) at the early developmental
stage. These cells migrate extensively and differentiate into
various tissues in the whole embryo. Bone is generated frommesoderm; however, most of the skull is derived from neural crest
cells. Recently, we established a method of differentiating ES cells
into maxillofacial bone via neural crest cells. We are conducting
research aimed at applying our findings to regenerative medicine
using iPS cells, adult tissue stem cells, and ES cells.
EMT is a phenomenon also observed in malignancy. Epithelial
cell-derived cancer cells acquire migration and invasive potency
after EMT, leading to metastasis. Some malignant cancer cells
have stem cell-like properties. Differences in the characteristics ofcancer stem cells and other cancer cells make the diseasedifficult to treat. Thus, our aim is to understand the characteristics of cancer stem cells and establish new treatment strategies.

Fig. Neuro-spheres derived from ES cells are induced to undergo osteogenesisby treatment with BMP4 and DEX. Calcium deposition is shown by red-stainingof alizarin, and upregulation of osteogenic marker genes during osteogenesis
is detected by semi-quantitative RT-PCR.

45

Yabumoto Department ofIntractable Disease Research
Glycosylphosphatidylinositol (GPI) is a glycolipid
attached to proteins and anchors them onto theplasma membrane. GPI-anchored protein has
various and important physiological functions in our
body. Why proteins have this peculiar structure like
GPI? Our research goal is to elucidate biogenesis,
transport and remodeling of GPI-anchored proteins
and understand its physiological significance in our
body.

Staff
Undergrad. Student 1 ／●How are GPI-anchored proteins(GPI-APs) regulated?

●Molecular mechanisms of GPI deficiencies.

GPI anchors are synthesized in the endoplasmic reticulum andattached to the C terminus of proteins during posttranslational
modification. GPI-anchored proteins are transported from theendoplasmic reticulum to the Golgi and further to the cell surface in a way that is regulated according to the features of GPI.
Recently, we identified the enzyme that can cut GPI-anchors,and showed GPI-APs can be secreted and work in the tissues
distant from its origin. This result indicates that GPI anchors
enable our body system to regulate where and when the protein works in a various way. We are currently studying the molecular mechanism to control the functions of GPI-APs. In addition, GPI anchor has specific carbohydrate side-chains and intriguingly, the chain varies among cells and proteins. We are interested in the physiological significance of this carbohydrate
chain and asking how this chain is synthesized in our cells.

We found that paroxysmal nocturnal hemoglobinuria (PNH) iscaused by somatic mutation of the X-linked PIGA gene, a genefor GPI-anchor biosynthesis. A recent report showed that atypical PNH is caused by somatic mutation of one allele of the
PIGT gene, a gene for GPI-anchor attachment, in combination
with a germline mutation in the other allele. Now, we are studying how unused GPI-anchor is involved in pathogenesis of
atypical PNH and try to find a cure for this disease.
We also identified a disease called inherited GPI deficiency(IGD) caused by the mutation of the GPI-anchor synthesizing
enzyme, PIGM. The recent whole exome sequencing analysis
using the next generation sequencer revealed 16 GPI-related
gene mutations responsible for IGD. To elucidate the molecularmechanisms of the pathogenesis of this disease, we developed
the system to analyze GPI biosynthesis and modification. Thissystem contributes to the IGD research in all over the world.
Our aim is to elucidate how GPI-anchors are involved in IGD
and find the way to overcome this disease.

Grad. Student 1

Taroh Kinoshita
Endowed Chair Professor
Dr. Kinoshita received Ph.D. from Osaka University in
1981. After working at Department of Bacteriology,
Osaka University Medical School and Department of
Pathology, New York University School of Medicine, heappointed as a Professor in RIMD in 1990. He served
as a Director of RIMD from 2003 to 2007. He concurrently serves as a Professor in Osaka University Immunology Frontier Research Center from 2007. From 2017,
he is in the current position.2017 Takeda Medical Prize,
2018 Medalwith Purple ribbon

Yoshiko Murakami
Endowed Chair Professor
Dr. Murakami received Ph.D. from Osaka University in
2001. After working at Osaka University Hospital andHyogo Prefectural Nishinomiya Hospital, she joined
Dept. of Immunoregulation at RIMD in 1998. She
became an Associate professor for Office of Combined
Program on Microbiology and Immunology (concurrently serve for Dept. of Immunoregulation and Immunoglycobiology in IFReC) in 2009. She is in the current
position from 2017.

Publication(1) Identiﬁcation of a Golgi
GPI-N-acetylgalactosamine transferasewith tandem transmembrane regionsin the catalytic domain. Hirata, T., et al.
Nat. Commun. (2018) 9:405.
(2) N-Glycan dependent protein folding
and endoplasmic reticulum retention
regulate GPI-anchor processing. Liu,
Y.-S., et al. J. Cell Biol. (2017) 217:585-599.
46(3) Phenotype-genotype correlations of
PIGO deﬁciency with variablephenotypes from infantile lethality tomild learning difﬁculties. Tanigawa, J.,et al. Hum. Mutat. (2017) 38:805-815.
(4) A GPI processing phospholipase A2,
PGAP6, modulates Nodal signaling inembryos by shedding CRIPTO. Lee,
G-H., et al. J. Cell Biol. (2016)
215:705-718.

(5) Pathogenic variants in PIGG cause
intellectual disability with seizures andhypotonia. Makrythanasis, P., et al. Am.
J. Hum. Genet. (2016) 98:615-626.
(6) Post-Golgi anterograde transport
requires GARP-dependentendosome-to-TGN retrograde
transport. Hirata, T., et al. Mol. Biol. Cell
(2015) 26:3071-3084.

GPI-anchor biosynthesis and the transport/remodeling of GPI-APs.

47

●Malaria vaccine targeting SERA5
Endwed Chair

Department ofMalaria Vaccine Development
Malaria is widespread in tropical and subtropicalregions, and millions of people, particularly in Africa,
remain at risk of disease and death despite substantial progress in malaria control. No effective malaria
vaccine has been developed or licensed. Ourlaboratory is undertaking basic research andconducting clinical trials on our own candidate
vaccine antigen gene.

The treatment of malaria patients is completely dependent
on the efficacy of anti-malaria drugs; however, drug-resistantparasites are emerging. Although a malaria vaccine is theideal weapon against this pathogen, vaccine development ishampered by genetic polymorphisms in candidate antigen
genes.
We have been focusing on the SERA5 molecule of P.
falciparum and developed malaria vaccine NPC-SE36 by
utilizing a recombinant SE36 protein. SE36 is a protein that is
highly expressed/produced in large amounts during parasite
growth in red blood cells. Epidemiological studies in malaria
hyper-endemic areas showed that children with antibodies
against SERA5 experienced few or no symptomatic/clinicalmalaria, albeit such children are a minority.
It was surprising that Ugandan adults that suffered numerous

malaria infections did not respond to vaccination with BK-SE36.
By contrast, malaria-naïve Japanese adults produced highlevels of antibodies. Moreover, in young Ugandan children thatexperienced few malaria episode, we observed good antibody
response. We obtained 72% protective efficacy 1 year
post-2nd-vaccination in a follow-up study of 6-20 years old in
the phase Ib trial. This suggests that our vaccine provides
better protection in younger individuals. We have conducted
Phase Ib clinical trial of NPC-SE36 in Burkina Faso in west
Africa in 2015-2017. Vaccine was well tolerated, and it was
found that the immune response in 1 year infants group wasmuch higher than 2-5 years child group. Currently we areconducting Phase Ib clinical trial of NPC-SE36 with CpG
adjuvant that stimulates innate immunity.

●Molecular strategy for malaria parasite survival and a function of SE36 protein

Staff
Prof.：Nirianne Marie Querijero Palacpac

Toshihiro Horii
Professor
Dr. Horii received his Ph.D. from Osaka University in 1981. After working at the Facultyof Science in Osaka University as Research
Associate, he was appointed Associate Professor at RIMD in 1991 and promoted Professor in 1999. He moved to the current department in 2019.

The malaria parasite develops highly sophisticated strategies
to evade the human immune system. One of the most difficult
phenomena encountered by those developing vaccines isgenetic polymorphism of vaccine candidate genes; that is,field-isolated parasites harbor different sequences from thevaccine candidate genes. Fortunately, SERA5 is highly homol-

ogous among malaria parasites worldwide. We haveanalyzed protective epitopes on SE36 protein. Recently wehave shown that SE36 protein tightly binds to host vitronectin
as cytoadherence molecule on the surface of parasite cell,merozoite, and vitronectin further binds to over 30 different
host proteins for molecular camouflage from host immune
system.

Fig. 1. Clinical trial of the NPC-SE36 malaria vaccine.
The vaccine was produced under GMP (Good Manufacturing
Practice) conditions at the Kanonji Institute of The Research
Foundation for Microbial Diseases of Osaka University.
(NPC-SE36 malaria vaccine was previously called BK-SE36
malaria vaccine.)

Publication(1) Molecular Camouflage of Plasmodium
falciparum Merozoites by Binding of Host
Vitronectin to P47 Fragment of SERA5.
Tougan T., et al. Sci Rep. (2018) 8:5052.
doi: (5)10.1038/s41598-018-23194-9.
(2) Antibody titres and boosting after
natural malaria infection in BK-SE36
vaccine responders during a follow-up
study in Uganda. Yagi M., et al. Sci Rep.
(2016) 6:34363. doi:
10.1038/srep34363.
48(3) Protective Epitopes of the Plasmodium
falciparum SERA5 Malaria Vaccine
Reside in Intrinsically Unstructured
N-Terminal Repetitive Sequences.Yagi
M., et al. PLoS One. (2014) 9:e98460.
doi: 10.1371/journal.pone.0098460.
(4) Phase 1b randomized trial andfollow-up study in Uganda of theblood-stage malaria vaccine candidate
BK-SE36. Palacpac N.M.Q., et al., PLoS
ONE. (2013) 8: e64073.
doi:10.1371/journal.pone.0064073(5) Plasmodium falciparum serine repeat
antigen 5 (SE36) as a malaria vaccine
candidate. Palacpac N.M., et al.,Vaccine. (2011) 29:5837-45. doi:
10.1016/j.vaccine.2011.06.052.
(6) Evidences of Protection Against
Blood-stage Infection of Plasmodium
falciparum by the Novel Protein Vaccine
SE36. Horii T., et al., Parasitol. Int.
(2010) 59:380-6. doi:
10.1016/j.parint.2010.05.002.

Fig. 2. Protective efficacy of NPC-SE36 malaria vaccine
Palacpac et al., Plos ONE. 2013; 8(5): e64073

49

Thailand-Japan Research
Collaboration Center

Until recently, it was believed that infectious diseases could
be conquered by developing chemotherapy regimens andvaccines; however, the recent worldwide emergence of new
infectious diseases and the re-emergence of infectious
diseases once considered to be under control have seriously challenged this notion. Since many infectious diseases
spread rapidly across national borders, it is clear that theycannot be controlled by the efforts of individual countries.
To overcome this, Osaka University founded the Research
Collaboration Center on Emerging and Re-emerging Infections (RCC-ERI) at the Thai National Institute of Health(NIH), Department of Medical Sciences, Ministry of Public
Health of Thailand, in 2005. The program is now in the third
phase (2015–2020) and is sponsored by the Japan Agency
for Medical Research and Development, which succeeded
to the second phase program named “the Japan Initiative for
Global Research Network on Infectious Diseases (J-GRID).”

Thailand-Japan Research
Collaboration CenterIn addition to basic and applied research into emerging andre-emerging infections, we aim to develop human resources. We also aim to establish an effective system that would(i) provide information that would help prevent the spread of
emerging and re-emerging infections, and (ii) promptly
activate a variety of countermeasures should such a disease
emerge, including the development of therapeutics and/or
vaccines. Finally, we wish to enter into collaboration withlaboratories from nations that neighbor Thailand so that wecan be on the “frontline,” with the capacity to respond quickly
to the global spread of infectious disease.

Section ofBacterial Infections

Tetsuya Iida (concur.)Professor

Kazuhisa Okada
SA Associate Professor
Dr. Okada received his Ph.D. from Osaka university
in 2005 and joined RIMD as a postdoctoral fellow
in that same year. He was appointed Lecturer ofThailand-Japan Research Collaboration Center on
Emerging and Re-emerging infections in 2015 afterworking as a Postdoctoral fellow from 2005 to2011 and an Asistant Professor from 2011 to 2015
in the same institution.

Publication(1) Simultaneous detection and quantiﬁcation of 19
diarrhea-related pathogens with a quantitative real-time PCR
panel assay. Wongboot W. et al., J Microbiol Methods. (2018)
151:76-82(2) Vibrio cholerae embraces two major evolutionary traits asrevealed by targeted gene sequencing. Okada K., et al. Sci.
Rep. (2018) 8(1):1631

The collaboration center is located in the campus of the Ministry of Public Health.

(3) Characterization of 3 Megabase-Sized Circular Replicons
from Vibrio cholerae. Okada K., et al. Emerg Infect Dis. (2015)21(7):1262-3.
(4) Cholera in Yangon, Myanmar, 2012-2013. Aung WW., et al.
Emerg Infect Dis. (2015) 21(3):543-4.
(5) Vibrio cholerae O1 isolate with novel genetic background,
Thailand–Myanmar. Okada K., et al. Emerg Infect Dis. (2013)
19:1015-7.

Enteric infectious diseases caused by various microbes
occur frequently in Thailand. However, there are nolarge-scale epidemiological studies of the etiology ofgastroenteritis in Thailand. In the Section of Bacterial
Infections, we are trying to develop effective diagnostic
tools to detect bacterial pathogens and devise measures
to prevent enteric infections, including those mediated byVibrio cholerae O1.

BSL-2 and BLS-3 laboratories in the center.

50

We collect and analyze fecal specimens from patientswith severe diarrhea admitted to leading hospitals
located in different parts of Thailand. We then try to detectspecific pathogens by real-time PCR analysis of bacterial genes and culture analysis. We also attempt to identify
unknown pathogens using TOF-MS or NGS. In cases ofcholera in Thailand or Myanmar, we will co-operate withgovernmental authorities to analyze V. cholerae isolates
to elucidate the route of transmission. We will also
undertake molecular and/or genomic characterization of
any identified pathogen. Our research goals are to develop methods for rapid diagnosis and to prepare countermeasures against what is still a challenging pathogen.

Detection of "pathogenic" agents from stool specimens of inpatientswith acute diarrhea and control subjects using multiplex real-time
PCR. Eight hospitals in different parts of Thailand participate in thisstudy.

51

Thailand-Japan Research
Collaboration Center

Thailand-Japan Research
Collaboration Center

Staff

Section of Viral Infections

Head, Prof. (concur.) : Tetsuya Iida ／Assoc. Prof.：Yukihiro Akeda

Staff
SA Assoc. Prof.：Atsushi Tanaka ／SA Assoc. Prof.：Hiroto Mizushima

Section of Bacterial Drug
Resistance Research(concur.) ／SA Asst. Prof.：Yo Sugahara ／SA Researcher : Noriko Sakamoto

Shigeyuki Hamada
Guest Professor

Masashi Tatsumi
SA Professor
Dr. Tatsumi received his Ph.D. from The Universityof Tokyo. After working at National Institute of
Health in Japan, Pasteur Institute and INSERM(French National Institute of Health and Medical Research) in France, he spent 12 years in National Institute of Infectious Diseases. After retirement, heserved as a chief advisor for JICA until taking his current position at RIMD in 2016.

Dr. Hamada received D.D.S. and Ph.D. degrees from
Osaka university in 1967 and 1971, respectively. He
became the Director of Dental Research, National
Institute of Health in 1980. Then he served as Professor of Microbiology in Osaka University Schoolof Dentistry from 1986 to 2005 and Professor of
Nihon University from 2005 to 2009. He joined RIMD
as SA professor in 2009 and later as guest professor.

Publication
Publication(1) Genome-Wide Screening Uncovers the Signiﬁcance ofN-sulfation of Heparan Sulfate as a Host Cell Factor for
Chikungunya Virus Infection. Tanaka A. et al J.Virol. 2017,
91 e00432-17(3) Evolutionary constraints on the norovirus pandemic variant
GII.4_2006b over the ﬁve-year persistence in Japan. Sato H
et al Frontiers in Microbiology 2017 8:410(2) Distribution of norovirus genotypes and subtypes in riverwater by ultra-deep sequencing-based analysis. Boonchan
M et al. Lett Appl Microbiol. 2017 65:98-104.

A variety of arboviruses are prevalent in Thailand locatedin the tropics, of which we investigate chikungunya fever
from an epidemiological, molecular biological, and immunological points of view. We focus on exploring thecellular factors necessary for viral replication with theexperimental system of knock-out and -in cell libraries ofsusceptible cells, and chikungunya pseudovirus. In
addition, we try to isolate virus from clinical samples andestablish the reverse genetics system to clarify thecharacteristics of zika virus, another arbovirus which has
been endemic long-termed in Thailand.
Another target is norovirus, a major cause of both
sporadic cases and outbreaks of nonbacterial acutegastoroenteritis in all age groups worldwide every year.
We investigate whether or not it is possible to predict the
genotypes of norovirus which are involved in new
epidemics by evolutionary phylogenic analysis withspecial reference to genotyping of epidemic strains. In
addition, recent epidemiological analysis has revealed
that "asymptomatic persons" who do not develop acutegastroenteritis even when infected with norovirus, mightplay a significant role as reservoirs in new outbreaks.
Noroviruses highly evolve with diversification of their52

genome through mutation and recombination, whichallows them to protect themselves from human hostimmunity and sustain their transmission in humancommunities. We try to clarify the retention and transmission of norovirus in asymptomatic persons, especiallyinvolvement in genome diversification to elucidate theactual condition of asymptomatic carriers. On the other
hand, we try to explore cellular factors necessary for virus
propagation in cells to establish a culture system of
norovirus, which remains still difficult to grow in vitro yet.

(1) Spreading patterns of NDM-producing Enterobacteriaceae inclinical settings in Yangon, Myanmar. Sugawara Y. et al.
Antimicrob Agents Chemother (2019) 63(3): e01924-18.
(2) PCR-dipstick-oriented surveillance and characterization of
mcr-1- and carbapenemase-carrying Enterobacteriaceae in a
Thai hospital. Shanmugakani R.K. et al. Front Microbiol(2019) 10:149.

(3) Genomic characterization of carbapenemase-producing
Klebsiella pneumoniae with chromosamally encoded bla
NDM-1. Sakamoto N. et al. Antimicrob Agents Chemother(2018) 62(12): e01520-18.
(4) Establishment of a dual-wavelength spectrophotometricmethod for analyzing and detecting
carbapenemase-producing Enterobacteriaceae. Takeuchi D.
et al. Sci Rep (2018) 8:15689.
(5) PCR-dipstik chromatography for differential detection of
carbapenemase genes directly in stool specimens.
Shanmugakani R.K. et al. Antimicr Agents Chemother (2017)
61(6): e00067-17.

Carbapenem-resistant Enterobacteriaceae (CRE), including
Klebsiella pneumoniae and Escherichia coli, are highly
resistant to carbapenems and many other antibiotics. The
rapidly increasing prevalence of CRE over the past decade
has increased concern in healthcare facilities and publichealth communities worldwide. Japan is no exception, eventhough the prevalence of CRE at this time remains low. Our
aim is to examine the epidemiological dissemination of CRE in
the Southeast Asian countries. Carbapenem resistance isusually carried by plasmid(s) that harbor genes encoding
carbapenemases, i.e., class A KPCs, class B metallo-β-lactamases (including IMP, VIM, or NDMs), or class D OXA-type
enzymes. We have attempted to isolate CRE from patients
admitted to leading hospitals in Thailand and Myanmar. CRE
isolates are identified by biochemical characterization or
MALDI-TOF-MS, followed by profiling using pulsed-field gelelectrophoresis (PFGE) and multilocus sequence typing(MLST). We then determine the whole genome sequence of
CRE isolates to identify the full plasmid and construct acomprehensive image of the relationships between isolates
based on MLST and phylogeny. By undertaking these genom-

ic epidemiological studies, we increase our understanding of
how CRE spread and may be able to identify potential
reservoirs.

Figure. A whole genome SNP-based phylogenetic tree of CRE
isolates from Myanmar. The inner colored regions define bacterial
species. Next outer colored regions denote the origins of isolates.
Colors and sizes of outer dots denote classes and numbers of
antimicrobial resistance genes harbored by each isolate.
53Thailand-Japan Research
Collaboration Center

Mahidol-Osaka Center for
Infectious Diseases

Thailand-Japan Research
Collaboration Center

Section of
Antiviral Research
Staff
SA Asst. Prof.：Akatsuki Saito(concur.)

The Mahidol-Osaka Center for Infectious Diseases (MOCID)
focuses on several tropical infectious diseases that are ofimportance to human health in Thailand. Mosquito-borne viral
infectious diseases such as dengue fever/dengue hemorrhagic fever and chikungunya fever are of particular interest.
We are currently developing rapid diagnosis kits and are
examining factors that affect disease severity. We would liketo improve the research skills of young scientists and increase
their interest in infectious diseases by collaborating with Mahidol University, which provides clinical samples.

Staff
Director of MOCID (concur.) : Prof.
Tatsuo Shioda
SA Asst. Prof. : Atsushi Yamanaka

Tatsuo Shioda (concur.)Professor
Dr. Shioda obtaind his B. Sc. from the University ofTokyo in 1982 and his Ph.D. form the same institution in 1990. After working at the Institute of Medical Science in the University of Tokyo and University of California San Francisco, he was appointed
as Associate Professor in 1997. He took his current
position as a Professor of RIMD in 2000.

Publication(1) Variation at position 350 in the Chikungunya virus
6K-E1 protein determines the sensitivity of detection ina rapid E1-antigen test. Aekkachai T. et al., Sci. Rep.
(2018) 8:1094(2) Diagnostic accuracy of a rapid E1-antigen test for
chikungunya virus infection in a reference setting.
Huits R., et al., Clinical Microbiology and Infection 24(2018) 78-81.

Publication(1) Capsid-CPSF6 Interaction Is Dispensable for HIV-1
Replication in Primary Cells but Is Selected during Virus
Passage In Vivo. Saito A., J Virol. (2016) 11;90(15):6918-35.
(2) Roles of Capsid-Interacting Host Factors in Multimodal
Inhibition of HIV-1 by PF74. Saito A., J Virol. (2016) 27;90(12):5808-23(3) Circulation of HIV-1 Multiple Complexity RecombinantForms Among Female Sex Workers Recently Infectedwith HIV-1 in Thailand. Saeng-Aroon S., et al., AIDS Res
Hum Retroviruses. (2016) 32(7):694-701.

(3) Sequence diversity of dengue virus type 2 in brain andthymus of infected interferon receptor ko mice: implications
for dengue virulence. Dhole P., et al., Virol J. (2016) 13(1):199.

Diagnostic kit developed by the MOCID.

(4) Detection of chikungunya virus antigen by a novel
rapid immunochromatographic test. Okabayashi T., etal. Clin Microbiol. (2015) 53(2):382-8.

Recently, climate change and urbanization haveincreased the risk of vector-borne diseases. Dengue andchikungunya viruses cause dengue fever/hemorrhagic
fever and chikungunya fever, respectively. Both viruses
are transmitted by Aedes mosquitoes. In 2014, there
was an outbreak of dengue fever in Tokyo. However, noantiviral drugs are available to treat these infections. Our
aim is to develop antiviral drugs against dengue andchikungunya viruses.
Four serotypes of dengue virus are distributed acrossthe world, and re-infection with different serotypes ofdengue virus leads to a more severe infection. We aim todevelop novel diagnostic tools that can differentiate
between the four serotypes of dengue virus.

54

Evaluation of CHIKV detection kit at Safdarjung Hospiral, Dehli,
India

Evaluation of CHIKV detection kit at the Institute of Tropical
Medicine Antwerp, Belgium

55

BIKEN Innovative Vaccine Research
Alliance Laboratories
Staff

As the recent Ebola virus outbreak in Africa and the worldwide influenza pandemic have powerfully demonstrated,society demands the development, production, and distribution of vaccines against infectious diseases. To meet thisstrong demand, The Research Foundation for Microbial
Diseases of Osaka University (BIKEN) and the ResearchInstitute for Microbial Disease, Osaka University (RIMD),
have established a new research organization, called The
BIKEN Innovative Vaccine Research Alliance Laboratories,
to promote the co-operative development of vaccines. Here,
we are developing new technologies to acquire basic
information required to design next-generation vaccines.

BIKEN Innovative Vaccine Research
Alliance Laboratories

Vaccine Creation Project
Staff
Postdoc.：Kazuki Misato ／Undergrad. Student 4 ／Grad. Student 3

Director, SA Professor

Koichi Yamanishi

Yasuo Yoshioka
SA Associate Professor
Dr. Yoshioka received his Ph.D. from Osaka University in 2004. He took his current positon at RIMD
from 2015 after working at National Institute of
Health Sciences, the Center for Advanced Medical
Engineering and Informatics and Grad. School of
Pharmaceutical Sciences in Osaka University.

Publication(1) Carbonate Apatite Nanoparticles Act as Potent Vaccine
Adjuvant Delivery Vehicles by Enhancing Cytokine
Production Induced by Encapsulated
Cytosine-Phosphate-Guanine Oligodeoxynucleotides.
Takahashi H, et al. Front Immunol. (2018) Apr 18;9:783.
(2) Distribution of silver nanoparticles to breast milk and their
biological effects on breast-fed offspring mice. Morishita Y,
Yoshioka Y, et al. ACS Nano. (2016) Aug 15.

A regular meeting between laboratories.
All members for this research project attend the meeting. Researchers
address their research topics in depth and take part in active discussions.

Experimental laboratories.
Researchers can move freely among three laboratories. All threelaboratories have common equipment.

56(3) Metal nanoparticles in the presence of lipopolysaccharides
trigger the onset of metal allergy in mice. Hirai T, Yoshioka Y,
et al. Nat Nanotechnol. (2016) 11(9):808-16.
(4) Silica and titanium dioxide nanoparticles cause pregnancy
complications in mice. Yamashita K, Yoshioka Y, et al. Nat
Nanotechnol. (2011) 6(5):321-8.

Most protein antigens such as non-living macromolecules or protein-subunit antigens evoke weak or undetectable adaptive immune responses. Therefore, todevelop effective vaccines it is necessary to develop
vaccine adjuvants and antigen delivery carriers. In
addition, to develop optimal (in terms of efficacy andsafety) vaccines for clinical application, it is important tounderstand the mechanism by which vaccines act on
the immune system. In this regard, our research is
focused on optimizing vaccines through drug delivery
systems and safety science. Our specific research
projects are:1) Development of vaccine adjuvants using comprehensive screening methods.
2) Development of antigen delivery carriers andadjuvants using nanotechnology.
3) To use these adjuvants and delivery carriers todevelop vaccines for infectious diseases.
57

BIKEN Innovative Vaccine Research
Alliance Laboratories

BIKEN Innovative Vaccine Research
Alliance Laboratories

Mucosal Vaccine Project

Vaccine Dynamics Project
Staff
Postdoc.：Yasunari Haseda

Shintaro Sato
SA Associate Professor
Dr. Sato received his master’s degree from Hokkaido university in 1999 and his Ph.D. from Osaka University in 2003. He took his current position in 2015
after working at RIMD as a Postdoctoral fellow andat University of Tokyo as an Assistant Professor.

Taiki Aoshi
SA Associate Professor
Dr. Aoshi received his M.D. from Hamamatsu University School of Medicine in 1999 and his Ph.D.
from the same institution in 2006. He was appointed current positon in 2015 after working at Washington University in St. Louis, NIBIOHN, and IFReC
in Osaka University.

Publication
Publication(1)Human Norovirus Propagation in Human Induced Pluripotent
Stem Cell-Derived Intestinal Epithelial Cells. Sato S., et al.
Cell Mol. Gastroenterol. Hepatol. (2018) pii: S2352-345X(18)30164-4(2) A Reﬁned Culture System for Human Induced Pluripotent
Stem Cell-Derived Intestinal Epithelial Organoids. TakahashiY., et al. Stem Cell Rep. (2018) 10(1):314.

Because most pathogens invade and infect their host
via mucosal tissues, mammals have established astrictly organized and dynamic immune system at mucosal surfaces. This system, named the mucosal immune
system, combats infectious pathogens. The development of mucosal vaccines, which activate mucosal andsystemic immune responses, is receiving increasing
attention. We have focused on epithelial cells, particularly M cells, which are professional antigen uptake cells
located in areas that come into contact with non-self-antigens. Our main research themes are:1)To identify new M cell-specific genes and elucidate
the mechanism of M cell antigen uptake.
2)To understand the aged mucosal immune systemand develop effective mucosal vaccines for older
people.
3)To establish an in vitro culture system for normal
and functional primary mucosal epithelial cells anduse it to screen for candidate mucosal vaccine
antigens and adjuvants.
58(3) Allograft inflammatory factor 1 is a regulator of transcytosis
in M cells. Kishikawa S., et al. Nat. Commun. (2017) 8:14509.
(4) Innate lymphoid cells regulate intestinal epithelial cell
glycosylation. Goto Y., et al. Science (2014) 345(6202):1254009.

(1) Quantifying the relative immune cell activation from wholetissue/organ-derived differentially expressed gene data.
Wijaya E., et al. Sci Rep. (2017) 7(1):12847.

(3) Plasmacytoid dendritic cells delineate immunogenicity of
influenza vaccine subtypes. Koyama S., et al. Sci Transl Med.
(2010) Mar 31; 2(25):25ra24.

(2) Development of non-aggregating poly-A tailed
immunostimulatory A/D-type CpG oligodeoxynucleotides
applicable for clinical use. Aoshi T., et al. J Immunol Res.
(2015) 2015:316364. doi: 10.1155/2015/316364.

(4) Bacterial entry to the splenic white pulp initiates antigen
presentation to CD8+ T cells. Aoshi T., et al. Immunity (2008)
Sep 19;29(3):476-86.

Vaccination, which utilizes the built-in “immune system”
in the body, is one of the most successful medicine forcontrolling microbial infections. The immune systemcomprises many different immune cells. T cells are oneof the most important immune cells that help to establish
protective immunity against many pathogens. In
addition, T cells are also involved in many non-infectious
conditions such as autoimmunity and cancer.
Although T cells are critically involved in many diseases,
current vaccines (with the exception of attenuated live
vaccines) cannot induce sufficiently strong T cell
responses. We are developing “T cell inducing vaccine”
through the studies of T cell epitope and T cell/antigen
presenting cell interaction. We are also developing
clinically applicable “nucleic acid adjuvants” that not only
induce strong Th1/CTL responses but also retain goodsafety profiles. We believe that the understanding of T
cell epitope, T cell/antigen presenting cell interactions,and the development of new adjuvants will enable us tomake safer and more effective T cell inducing vaccines in
the near future.
59

Animal Resource Center
for Infectious Diseases

Office for Research Promotion
Staff
Head Prof.: Masahito Ikawa

The researchers at RIMD are supported by administrative functions provided by the Office for Research Promotion. The aim of this office is to promote
communication among researchers and to develop human resources withexpertise in scientific research. The office also communicates RIMD
research achievements to the general public.

Asst. Prof.: Keisuke Shimada
Asst. Prof. (concur.): Haruhiko Miyata

To study infectious diseases and cancer, it is important toanalyze interactions between pathogenic factors and thehuman body. Animal models are indispensable for biomedical
research, particularly since molecular biology and biotechnology methods can be used to generate genetically modified
mice that aid our understanding of the molecular mechanisms
underlying such diseases. Experimentally infected animals
and genetically engineered animals used for these purposes
should be managed in a suitable, safe, and controlled manner.
The Animal Resource Center for Infectious Diseases is aunique facility that was established in 1967 to meet theserequirements.
The center is equipped with pass-through-type autoclave
systems and HEPA filtered air exchange systems to minimize
the risk of contamination so that infected or geneticallyengineered animals are maintained in a safe environment.
The animals are housed in three areas: SPF (specific pathogen free), BSL (biosafety level) 2, and BSL3. Before gaining
access to restricted areas, researchers must take an official
orientation and submit a research plan for committee review.
The condition of the animals is monitored regularly.
Our facility provides the following services: generation ofgenetically manipulated animals, in vitro fertilization, andcryopreservation of mouse strains (Table 1). The facility
provides these services in co-operation with the Department
of Experimental Genome Research.

Biosafety level 3 room.
The room is used for research involving disease model animals at
biosafety level 3. Hemorrhagic fever with renal syndrome-causing
virus (HFRSV) was isolated in this area. In addition, animal experiments involving Zika virus, SARS, and Acquired Immune Deficiency Syndrome (AIDS), can be handled in this facility.

60

Asst. Prof. (concur.): Taichi Noda
SA Asst. Prof. (concur.): Daiji Kiyozumi
SA Asst. Prof. (concur.): Tsutomu Endo

Staff
Head, Prof. (concur.) : Masato
Okada

The office provides the following services:

Assoc. Prof. : Ryo Iwamoto

1. Manages of International Forums:
Table 1 *Tg, Transgenic; KO, Knockout; IVF, in vitro
Fertilization; ET, Embryo transfer.
IVF/ETTG

KO, KI

-2003

261

228

50

2001- 2003

443

104

57

2004-2006

331

43

69

2007-2009

216

22

74

2010 - 2012

388

55

152

2013 - 2015

580

50

242*

2016 - 2018

505

21

191

Asst. Prof. : Saya Nakagomi

・Awaji International Forum on Infection and Immunity・International Symposium of the Institute Network for Biomedical
Sciences

2. Organizes seminars and lectures at RIMD.
3. Organizes lecture programs for undergraduate and graduate
students.
4. Organizes orientation and Lab Tours for RIMD and IFReC for
candidates looking to fill graduate school/post-doctoral positions.
5. Analyzes institutional research activity and performance.
6. Covers public communications and outreach.
7. Oversees the Taniguchi Fellowship Program for ASEAN students.

* Includes lines generated using the CRISPR/Cas9
genome editing system.

Awaji International Forum on Infection and Immunity

Advanced Seminar Series

Poster session in RIMD Result Presentation

RIMD Result Presentation Academic prize awardee

Winterschool for High school teachers

RIMD booklets and newsletters

Buildings at the Animal Resource Center.
Building A (in front of the chimney, built in 1967, two-story).
Building B (rear right of the chimney, built in 1978, four-story).
Building C (on the right side of Building A, built in 2009, four-story).

61

Common Research
Facilities

Central Instrumentation
Laboratory

Staff
Head, Prof. (concur.) :Hiroaki Miki
Assoc. Prof. :Shinji Higashiyama

Common Research
Facilities

The Central Instrumentation Laboratory was established in 1959. When equipment was lacking in many laboratories, researchers brought their machines
together and co-operated with each other. Now, various pieces of precisionapparatus and high performance machines are available in the laboratory at all
times. These include ultracentrifuges, transmission and scanning electron microscopes, a Biacore system, cell analyzer/sorters, an DNA sequencers, and mass
spectrometers. Also, large cell storage tanks equipped with automatic liquid
nitrogen supply systems and a specified chemical treatment room are alsopresent. In addition, professional technicians are employed to maintain andmanage these devices, as well as to provide services, education, and training fornewcomers. They also provide in-house services such as cell sorting, mass
spectrometry-based protein identification, electron microscope image capture,and DNA sequencing. As experimental machines become more and more
complicated, the services provided by specialist staff are essential for ongoing
research at the institute.

Assoc. Prof. :Naohisa Goto

Central Laboratory for Biological
Hazardous Microbes

This BSL-3 laboratory was set up in1983 to ensure the safe handling of
biologically hazardous microbes such as
hemorrhagic fever with renal syndrome(HFRS) virus. All experimental studies
using hazardous microbes, such as HIV,should be handled in this laboratory. The
laboratory is a three-story building with
550 m2 of floor space. The facilities aredesigned to protect researchers from
pathogenic infection and to prevent the
spread of biohazardous pathogens
outside the building. The supply of fresh
air is regulated to keep the room interiors
at negative pressure. High-quality filters
are installed on the exhaust outlet tominimize microbial contamination of theenvironment. Each room is equippedwith safety cabinets and autoclaves tosterilize used material before disposal.
Researchers must be approved by the
Biosafety Committee before they use
this laboratory. Various microbes, including HIV, SARS corona virus, and scrapie
agent, are studies in this facility.

Central Laboratory
for Biological
Hazardous Microbes

Staff
Head, Prof. (concur.) :Tatsuo Shioda

Administration
General Affairs Section
Accounting Section
Research Cooperation Section
Central Instrumentation Laboratory staffs

Radioisotope Labolatory

The radioisotope (RI) laboratory was established in 1967 and was designed forbiomedical experiments involving RIs. Now, RIMD researchers perform RI
experiments in the RI Laboratory at the Immunology Frontier Research Center at
9F, the Central Laboratory for Biological Hazardous Microbes at 1F, and theradiation exposure room in the North building at 1F. Facilities include a RI stockroom, a distribution room, a tissue culture room, and an area for RI measuring
equipment. Safety requirements are met by a stringent security system thatinvolves the use of ID cards and the computerized management of RIs.

Staff
Head, Prof. (concur.) :Hiroaki Miki

62

63

About RIMD

RIMD History

KEY PERSONThe Research Institute for Microbial Diseases (RIMD) was established in 1934 to study microbial andinfectious diseases, the immune system, and cancer. The RIMD of today is the result of the hard
work and amazing achievements of many researchers over the years.

Tenji
Taniguchi

Gendo
Yamaguchi

Professor of Bacteriology at the
Osaka Medical school. He played ahuge role in the foundation of RIMD
as he emphasized the need for a
research institute in the KANSAI areathat focused on microbial or infectious diseases.

A successful businessman in the
KANSAI area. He gave back to thecommunity by offering his property
for public beneﬁt services andtemples. He donated 200,000 yen
to establish RIMD.

RIMD buildings in 19342005

Three centers for specialized research on infectious disease andgenome information launched. The Research Collaboration Centeron Emerging and Re-emerging Infections in Thailand was founded

RIMD buildings
The Takeo Tuberculosis
in 1934
research Center

RIMD
History

1934

The Osaka Leprosy InstituteResearch Institute for Microbial Diseases opened
The main RIMD
building at Dojima
in 1934

RIMD was founded through a merger of the Research Center forCommunicable Diseases (Osaka Medical School), the Takeo
Tuberculosis Institute (donated by Mr. Jiemon Takeo), and the
Osaka Leprosy Institute (donated by an anonymous benefactor).

2000s

1970s

1980s

Kumao Toyoshima

Developed a chickenpox
vaccineElucidation of the Innate
Immune System

MichiakiTakahashi

ShizuoAkira

Discovereda viral oncogene

2008

Selected for funding by the Global COE programson the theme of “Frontier Biomedical Science
Underlying Organelle Network Biology”

2015

BIKEN Innovative Vaccine
Research Alliance
Laboratories was launched

HISTORYKEY PERSON

1950s

Discovered Vibrio parahaemolyticus

Tsunesaburo Fujino

1960s
Discovered
cell fusion

Developed
a measles vaccine

Yoshio Okada

Yoshiomi Okuno

1967

RIMD moved to the Suita Campus
RIMD buildings in 1967

1993

RIMD Hospital was
merged with
Osaka University
Hospital

2003

Selected for funding by the 21stCentury COE programs on thetheme of “Combined program on
microbiology and immunology”

2007

Immunology Frontier
Research Center (IFReC)
was founded2010

Approved as a Joint Usage /Research Center by Ministry of
Education, Culture, Sports,
Science and Technology

The Suita Campus, Osaka University

1798
The Epochs
in Biology

Development of
Smallpox vaccine(The first successful
vaccine developed)
E. Jenner

1919

1957

K. Yamagiwa

F.M. Burnet

Proved chemical
carcinogenesis

Clonal selection theory
in immunology

1975

Production of monoclonal
antibodies using cell fusion
technique.

1979

1981

Discovery of oncogene, c-Src

Establishment ofEmbryonic Stem Cells(ES cells)

J.M. Bishop, H.E. Varmus

2003

Human Genome Project completed

M. Evans, M. Kaufman

C. Milstein

HISTORY

1870-1880

1928

1953

1965

L. Pasteur, R. Koch

A. Fleming

J. Watoson, F. Crick

H. Khorana

Establishment of
the germ theory of disease64

Discovery of Penicillin(The first antibiotics)

Discovery of
the DNA structure

Revealed
Genetic code

1977

Discovery of the genetic
mechanism to produce
antibody diversity
S. Tonegawa

1980

Eradication of smallpox
was declared by WHO

1996

Dolly the sheep was born
(The first cloned mammal)

2006

Establishment of
Induced Pluripotent Stem Cells(iPS cells)
S. Yamanaka

65About RIMD

RIMD Awards

The 3rd Study Group for Mycobacteria Best Presentation Award
Naoya Nishimura Dept. of Molecular Immunology

2018

The 21st JSI Award ( Japanese Society for Immunology )Sho Yamasaki Dept. of Molecular Immunology

Suita City Mayor's Commendation Excellent Hazardous Materials Security Superintendent Award
Shinji Higashiyama Central Instrumentation Laboratory

2018.42018.12

Japan Medical R&D Grand Prize.
Masahiro Yamamoto, Dept of Immunoparasitology

2018.1215th JSPS Prize

The Commendation by the Minister of Education, Culture, Sports, Science and Technology
The Young Scientistsʼ Prize
Miwa Sasai Dept. of Immunoparasitology

2018.11Masahiro Yamamoto, Dept of Immunoparasitology

2018.122018.4

The 34th Annual Meeting of the Japan Society of Drug Delivery System Outstanding Presentation Award
Kazuki Misato Vaccine Creation Project2018.6JVBMO Young Investigator Travel Award for The 20th International Vascular Biology Meeting(IVBM2018)
Tomohiro Iba Dept. of Signal Transduction

2018.6JVBMO Young Investigator Travel Award for The 20th International Vascular Biology Meeting(IVBM2018)
Yohei Tsukada Dept. of Signal Transduction

2018.6JVBMO Young Investigator Travel Award for The 20th International Vascular Biology Meeting(IVBM2018)
Fumitaka Muramatsu Dept. of Signal Transduction

2018.6

Best International Abstract Award, 51st Annual Meeting of the Society for the Study of Reproduction
Yoshitaka Fujihara Dept. of Experimental Genome Research

2018.7

Best International Abstract Award, 51st Annual Meeting of the Society for the Study of Reproduction
Julio Castaneda Dept. of Experimental Genome Research

Miwa Sasai(Dept. of Immunoparasitology)
The Commendation by the MEXT,
The Young Scientists’ Prize

Masahiro Yamamoto (3rd from left, in the back raw)
Japan Medical R&D Grand Prize.

2018.7

Poster Presentation Award, JVBMO
Hisamichi Naito Dept. of Signal Transduction

2018.9Poster Presentation Award, JVBMO
Hiroyasu Kidoya Dept. of Signal Transduction

2018.9

Best Talk Award, Grant-in-Aid for Scientiﬁc Research on Innovative Areas - Platforms
for Advanced Technologies and Research Resources, Platform of Advanced Animal Model Support
Hiroyasu Kidoya Dept. of Signal Transduction

2018.9

Excellence Award, 2018 Uehara H. pylori Award
Hitomi Mimuro Dept. of Infection Microbiology

2018.92018 International Symposium of Innovative Research and Graduate Educationin Biomedical Sciences Best Presentation Award
Woei-Yaw Chee Dept. of Oncogene Research

2018.9Medal with Purple Ribbon
Taroh Kinoshita Yabumoto Department of Intractable Disease Research

66

2018.1167

About RIMD
Collaboration with relevant institutes and universities●Collaboration with BIKEN foundation and Immunology Frontier Research Center (IFReC)●MEXT Joint Usage / Research Center

RIMD was certified as a “Joint Usage/Research Center” by the Ministry of Education, Culture, Sports, Scienceand Technology in Japan (MEXT) in 2010. The “Joint Usage/Research Center” is a sharing system firstorganized by MEXT in 2008 and which allows Japanese researchers to use facilities, equipment, anddatabases at inter-university research institutes.
The aims of RIMD as “Joint Usage/Research Center” are to promote research and develop human resourcesin the fields of immunology, bacteriology, and oncology. We provide
specialized facilities equipped with BSL2 and 3 laboratories in Animal
Resource Center and Infectious Diseases and Central Laboratory for
Biological Hazardous Microbes. In addition, Genome Information Center is forgenome research with Next Generation Sequencers and support researchers
to analyze genomes of organisms.
We also hosts international symposiums such as Awaji International Forumon Infection and Immunity to share research achievements and facilitatecommunication among researchers.

RIMD and IFReC conducts world-class researches in biological fields including microbiology and immunology. RIMD and
IFReC collaborate each other to promote researches and foster talented human resources in these fields.
The BIKEN foundation develops vaccines, thereby to translate the research achievements in of RIMD to the society. In
addition, the foundation is dedicated to promote basic research through the Taniguchi Memorial Scholarship program andthe BIKEN Center for Innovative Vaccine Research Alliance Laboratories.

Animal Facility

Triangle
Relationships

on Infectious Diseases
and Immunology

Joint Usage/
Research Center
Next Generation Sequencer and server

World PremierInternational Research Centeron immunology

Awaji International Forum on Infection and Immunity●International Collaborations
RIMD researchers conduct international collaborative Projects that involve researchers from various contries. FIMD also
concludes academic agreements with four institutes and universities.

International collaborative projects
Year

2010

2011

2012

2013

2014

2015

2016

Projects

24

42

49

42

32

35

43

The Research Foundation for Microbial Diseasesof Osaka University

Academic agreements

68

Country

Institute / University

Starting date

ThailandBamrasnaradura Infectious Diseases Institute2013/2/15〜

Indonasia

Airlangga University (Faculty of Medicine)2013/7/31〜

Lithuania

Vilnius University (Faculty of Medicine)2017/6/16〜

U.S.A.

Baylor College of Medicine (Departments of Pathology & Immunology)

2017/4/10〜

69

About RIMD
To Develop Human Resources Globally

Seminars and Events●Clinical Training Course on Tropical Infectious Diseases in the Thailand

We organize conferences and seminars to facilitate communication among researchers. We also organize an
outreach event to provide accurate information about our research findings and achievements.

The age of global travel means that people can spread pathogens worldwide. Infectious diseases are now a
global problem that extends beyond national borders. In Japan, there is a compelling need for experienced
specialists to study these infectious diseases.
Since 2009, RIMD, together with the School of Medicine at Osaka University, has provided a clinical training
course on Tropical Infectious Diseases in Thailand. The course provides medical doctors with clinical training
on the diagnosis and treatment of infectious diseases and is supported by hospitals in Thailand. This training
course provides a valuable opportunity for Japanese clinicians to gain clinical experience from hospital staff
operating in a high-incidence area. Over 50 doctors participated in this training course, and the alumni are
conducting basic/clinical research into infectious diseases or working for Medicines Sans Frontieres andvarious governmental organizations.

●Events for Researches

International Conferenes

Awaji International Forum on Infection and
Immunity（http://awaji-forum.com/）
International Symposium of the Institute Network(http://awaji-forum.com/)

BIKEN Monthly Seminar

Held monthly, except August and December.
Young researchers present their recent researchfindings.

http://tmtc.biken.osaka-u.ac.jp/intention/index.html

Awaji International Forum on Infection and Immunity

2018 ᖺ 2 ᭶ 27 ᪥㸦ⅆ㸧4 ᫬㹼5 ᫬
Tuesday, February 27, 2018

ᚤ◊⼥ྜᲷ㸯㝵

4:00 – 5:00pm

㇂ཱྀグᛕㅮᇽ

Taniguchi Memorial Hall, 1F, Integrated Life Science Bld.

Advanced Seminar Series on Microbiology
and Immunology

Lecture series hosted by the Office for Research
Promotion. Leading researchers in the field ofMicrobiology and Immunology are invited to thislecture series.

➨ 573 ᅇᚤ◊㞟ㄯ఍
Biken Monthly Seminar

1. Phosphatidylserine receptor Tim4 greatly

enhances TAM receptor dependentefferocytosis

Yuichi Yanagihashi / ᰗᶫ㸦ච␿࣭⏕໬Ꮫศ㔝/♸୍

IFReC㸧

2. Immuno-modulating peptides for vaccine

development

Yasuo Yoshioka / ྜྷᒸ㟹㞝

㸦BIKEN ḟୡ௦࣡ࢡࢳࣥ༠ാ◊✲ᡤ࣡ࢡࢳࣥ๰ᡂࣉࣟࢪ࢙ࢡࢺ㸧ྖ఍㸸 Sugiko Watanabe/Ώ㑓 ࡍࡂᏊ

(㑇ఏᏊ⏕≀Ꮫศ㔝)

Hospitals participating in clinical training in Thailand.
Doctors can learn directly from local staff.

Mae Sot

Bridge Seminar

Seminar series hosted by young researchers at
RIMD.

㐃⤡ඛ㸸ᚤ⏕≀⑓◊✲ᡤឤᰁ⑕Ꮫච␿Ꮫ⼥ྜࣉࣟࢢ࣒ࣛ᥎㐍ᐊ㸦tel: 8260㸧
Contact: Office of Combined Program on Microbiology and Immunology, RIMD

Biken Monthly Seminar

Advanced Seminar Series

Udon Thani＜Hospitals for clinical training in Thailand＞
Khon Kaen

Bangkok

Doctors gain hands-on experienceduring the training course.

㸨ᮏ௳ࡣࠊ་Ꮫ⣔◊✲⛉ ಟኈ࣭༤ኈㄢ⛬ࡢ༢఩ㄆᐃࢭ࣑ࢼ࣮࡛ࡍ
㸨㸨᪥ᮏㄒ࡛⾜ࢃࢀࡲࡍࠋThe seminar is conducted in Japanese.

ThailandMae Sot：

Mae Sot General Hospital
Mae La refugee camp
Mae Tao Clinic
Maeramad Hospital
Shoklo Malaria Research Unit
Udon Thani：

Bangkok：

Ramathibodi Hospital, Mahidol University
Queen Sirikit National Institute of Child Health●Outreach Events
We organize outreach Events and Exhibitions for the non-scientific community. In addition, we try to encourage young
students, including high school students and junior high school students, to take an interest in scientific research.

Khon kaen：

Srinagarind Hospital, Khon Kaen University
Khon Kaen General Hospital

Udon Thani Genelas Hospital●Taniguchi Scholarship: International Students Scholarship Program

RIMD established a scholarship program for Students from ASEAN
countries to study at RIMD as graduate students and provide
leadership and support to become independent researchers.
Particularly excellent candidates will be offered a regular faculty
position at RIMD after they obtained Ph.D.. This new scholarshipprogram aims to significantly contribute to the development ofscience by training world-leading researchers from the international
students learned at RIMD.

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Osaka University ICHO Festival

Summer Seminar for high school studets71

> Osaka University COOP guidance book

For Students andResearchers who wants
to study in RIMD
RIMD is one of the world’s foremost institute in immunology, microbiology and cancer research.
We also conduct research in various bioscience related fields including gene engineering,genomic science and bioinformatics. We welcome motivated grad-students and researchers fromaround the world.

The Osaka University COOP is a non-profitable organization for students andstaffs in Osaka university. They provide stores, cafeterias andother life supports including housing and traveling.

http://www.osaka-univ.coop/english/index.html

Information in Japanese Government or Organization> Study in Japan Comprehensive Guide by The Ministry ofForeign Affairs of Japan
http://www.studyjapan.go.jp/en/index.html

students or post-docs may need to decide the lab to join and then ask PIs how to belong to RIMD.

> Websites of Japanese Embassies in your country
http://www.mofa.go.jp/about/emb_cons/mofaserv.html

The Orientation and lab tour would be held in May every year. Please check our website for detail.

> Japan Student Services Organization (JASSO)

The way to join RIMD would be different depends on the situation. Candidate for grad-schoolwww.biken.osaka-u.ac.jp/en/recruit

An independent administrative institution established under the MEXT,
comprehensively administers support programs forinternational students including scholarship loan programs.

http://www.jasso.go.jp/en/index.html> Gateway to study in Japan by JASSOInformation in Osaka University website> Osaka University website for Global Affairs
http://www.osaka-u.ac.jp/en/international> Osaka University website for International Students
http://www.osaka-u.ac.jp/en/for-student> Osaka University Support Office for international Students
https://iss-intl.osaka-u.ac.jp/supportoffice/> Osaka University Brothers and Sisters Program (BSP)

Information in Japanese, English, Chinese, Korean, Indonesia, Thai, Vietnamese

http://www.g-studyinjapan.jasso.go.jp> Japanese Government scholarship by MEXT
http://www.studyjapan.go.jp/en/toj/toj0302e.html> Suita International Friendship Association

A public interest Incorporated Foundation to
support citizen’s international exchange activities and provide assistance toforeigners living or Studying in Suita city.

http://suita-sifa.org/en/

An International-exchange circle organized by Osaka University
Students to support international students.

RIMD and IFReC conducts world-class researches in biological fields

http://www.bsp-ou.net/

collaborate each other to promote researches and foster talented humanincluding the fields of microbiology and immunology. RIMD and IFReC
resources in these fields.
The BIKEN foundation develops vaccines, thereby to translate the researchachievements in of RIMD and IFReC to the whole of society. In addition, thefoundation is dedicated to promote basic research by through the Taniguchi
Memorial Scholarship program and the BIKEN Center for Innovative Vaccine
Research Alliance Laboratories.

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73

Grad Students Studying in RIMD
Why RIMD?
A few years ago, I was lucky to experience Japan’s superadvanced research as an exchange student at NIPS
(National Institute for Physiological Sciences) andUniversity of Tsukuba. Since then, my interest to Japannot only research but also its cultures and language hasdeveloped. Apart from that, during my bachelor course, I
studied bacterial genetics and physiology which drove
my interest to the mechanism of bacterial infections inhuman. After finishing study I thought myunderstanding on this field was insufficient. Therefore, I
set the dream to pursue graduate study. Strong
engagement with Japan, lead me to choose Japan as
study destination. Fortunately, universe supported me.
There was a scholarship opportunity from RIMD, one of
the foremost research institution with one of theresearch field is bacterial infection. In addition, RIMD
seems to offer very good environment, advanced
facilities, and most importantly it has many world-levelresearchers on each field. With those reasons, I decided
to join RIMD and I would say it was one of the best
decision I have ever made.

A day in the life
My experience as a graduate student at RIMD has beenpleasant, mainly because of the limitless support andencouragement of the lab members and supervisor.
Performing research becomes main activity to spend aday, it is always challenging yet rewarding. During thatprocess, we are encouraged to come up with ideas, tothink critically, to solve problems, to persist, and to learn
other aspects necessary to become a competentresearcher. RIMD also provides chances to interact withwell-known researchers through various interesting
seminars. Furthermore, I find that living in Osaka is fun
and always been decent place to explore. Since I likesport and culinary, sometimes on the weekend I playbadminton or travel around to try different foods andsnacks. Lastly, as Japanese is mostly used duringexperiment or daily life, I
keep forcing myself to speak
Japanese everyday with other lab
members, and I am grateful that they are
extremely supportive to me.

Research Interest
I was fortunate to be accepted into Prof. Horiguchi’s
team in which one of the big goal is to understand theentire picture of the bacterial infection from each particular
steps. Various human or animal pathogens, such as
Bordetella spp did not emerge suddenly, instead it underwent
evolutionary steps which eventually developed their adaptationfrom environmental bacteria to human or animal pathogen. Since
the focus of the pathogenic bacteria study is mostly done during
host infection, the information regarding their life style outside themammalian hosts is still limited. This issue becomes my current
research topic. To be specific, I am trying to examine the nature ofB. bronchiseptica (part of Bordetella spp) life style and determine thepossibility of the bacteria interaction with protozoan predators,
especially amoeba. Furthermore, understanding the molecularmechanism of this interaction will bring new insight on how thebacteria obtain the ability to establish their infection in human or
animal hosts.

Message for young students
Exploring the whole new environment will always be
adrenaline-rush experience. However, without new challenges, wecannot see how far we have improved. It is the same with pursuing
graduate study, it is challenging and is demanding high effort andpersistence yet really worth doing. Therefore, I encourage to all
young mind out there to tenaciously pursue your passion and work
hard for it. If you have interest on basic research and may think towork as researcher in the future, bring that passion to RIMD and see
how far you can advance yourself. Nothing better than turning thepassion into real work because it always helps us to stay focus, feelexcited, and become more passionate on what we do. Finally, I hopethe best of luck for them who want to get in to RIMD and Osaka
University.

Dendi Krisna Nugraha

Department of Molecular Bacteriology (Horiguchi Lab)
Doctoral Course in Graduate School of Frontier Biosciences,
Osaka University
BA: Microbiology, Bandung Institute of Technology
MA: Graduate school of Frontier Biosciences, Osaka University
from Bandung Institute of Technology, Indonasia

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Why RIMD?

Research Interest

I used to be a pediatrician in China and I wanted to help
all of my lovely patients overcome their sickness.
However, there are still a lot of incurable diseases thattake many lives away. The mission of a clinical doctor isto help patients, but what if I become a researcher?
Could I help more people and save more lives? After
thinking about this, I decided that I wanted to make myown contribution to the medical development. I chose tofocus on infectious diseases which are the mostcommon but dangerous illnesses for children. RIMD is
one of the most famous institutes which concentrates
on microbiology and immunology. It can offer me many
opportunities to learn cutting-edge knowledge and help
me achieve my goal.

I was very lucky to be accepted by the department of
Molecular Virology, which focus on Hepatitis viruses
and flavivirus virus. Now I’ m doing research about
hepatitis B virus (HBV). Up until now, Chronic hepatitis B
virus infection affects approximately 240 million people
in the world. However, the present therapeutics fail toprovide a cure for the vast majority of patients, because
the Covalently closed circular DNA (cccDNA) in the
nucleus of infected cells cannot be eliminated, and that
may result in persistence and relapse. In HBV life cycle,
cccDNA is transformed from rcDNA after it enter the
nucleus. We could interrupt HBV replication if thenuclear transport step is blocked. Therefore, I’ m trying
to identify the host factor involved in HBV nuclear
transport, which may lead to the development of novel
antiviral strategies and drug targets.

A day in the life

I was definitely a beginner at experiments when I firstcame to the lab. My professor and seniors in our lab
taught me various techniques with great patience.
Without their help, I wouldn’t be able to adapt to a new
study life in a foreign country that soon. I also attend
lots of interesting seminars which help broaden myhorizon. I’m working hard on weekdays and playing hardin the holidays. In my opinion, studying abroad is not
only about doing experiments, but also about having
real experiences with the world beyond my border. In myspare time, I’d like to travel around Japan and experience
different languages, cultures and societies. I have been
to many places such as Kyoto, Hiroshima, Gifu, Tokyoand so on. Every day I spend here is very rich andcolorful, and all of these experiences have become
precious treasures in my life.

張Message for young students“Never forget why you started and don’ t be afraid of
failure.” This is the sentence I usually use to motivate
myself. Research sometimes can be boring. It is a roller
coaster of ups and downs. We are working hard day andnight, looking for a spark of light in the dark, while thefuture is unknown and all the effort might be in vain.
It’ s easy to give up in the harsh times, but the reason
we started can ignite our passion again. We will achieve
our goal sooner or later if we stick to it, whereas there isnothing but failure once we give up. Don’ t be anxious toachieve quick success or get overnight results, be atpeace with yourself, love the process and you’ ll love
what the process produces brings you.

赫

Department of Molecular Virology(Matsuura Lab.)
Doctral Course in the Graduate School of Medicine
BA：Clinical Medicine, the Capital Medical University, China

75

BUILDING AREA

RIMD STAFF●Staffs●Graduate Students①②

Professor

14

Graduate school of Medicine

47

7

Endowed Chair Professor

2

Graduate school of Science

6

10

Associate Professor

19

Graduate school of Pharmaceutical Science

3

11

Assistant Professor

22

Graduate school of Frontier Biosciences

19-

SA Professor

3

SA Associate Professor

4

SA Assistant Professor

9

SA Researcher

8

SA staff

40

Educational Support Staff

3■①Doctoral Program■②Masterʼ s Program●Research Fellows and Research Students

Technical Staff

20

Special research students

5Part-time Gneral & Technical Staff

36

Research students

7

Administrative Staff

22

JSPS Research fellows

1

Total 202
(SA: Specially Appointed)⑦ Central Laboratory for
Biological Hazardous Microbes
and (back)⑤⑥ Animal Resource Center(left,front)① Main Building (left)⑪ Cutting-edge Research
Building for Infectious
Diseases (right)② South Building

ACCOUNTS
Site Area 36,036㎡
Building Area 8,702㎡

Cooperation Research
111,695

Collaborative Research
1,615,087

Management Expenses Grant(Non-Personnel)
474,951

3

7

12

13

6
9

8

5

4
10
1

Management Expenses Grant(Personnel)
837,822

11

Total

3,560,182

2

unit: thousand yen

MEXT Research Grants
407,565
Other Research Grants
13,740
Health and Labor Sciences Research Grants
3,100

76

Gross Floor Area 39,945㎡

Building nameTotal
floor numbers

Building
area (㎡)

Total floorarea(㎡)■①Main Building

7

1,706

6,397

■②South Building

2

409

945

■③North Building

3

492

1,252

■④Annex

2

768

1,548

■⑤Animal Resource Center A

2

640

1,391

■⑥Animal Resource Center B

4

355

1,425

■⑦Central Laboratory for
Biological Hazardous Microbes

3

241

550

■⑧Central Instrumentation Laboratory

2

378

504

■⑨Depository for Dangerous Chemicals

1

160

160

■⑩Integrated Life Science Building

10

1,072

9,258

■⑪Cutting-edge Research Building
for Infectious Diseases

9

973

7,448

■⑫Animal Resource Center C(belonging to IFReC)

4

738

2,482

■⑬IFReC Building

9

770

6,585

Donations for Research
96,222

77

ACCESSMAP▶Osaka University

Suita Campus

8

Bus Stop
Handai Guchirch
Support RIMD Reseae in science--Be part of the quest

2
1

3
East Gate

Senri Gate
West Gate

Bus Stop
Handai Honbu
Mae

9

6

4

7

Handai
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research in this fie
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How your donations

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Kita-Senri

Main Gate

1 Research Institute for Microbial Diseases

4 Graduate School of Medicine

7 Administration Bureau

2 Immunology Frontier Research Center

School of Frontier
5 Graduate
Biosciences

8 The Institute of Scientific

3 Graduate School of Engineering

6 Osaka University Hospital

MINOHCampusKita-Senri
Ishibashi

TOYONAKA
CampusHotarugaike

Osaka (Itami)
AirportSUITA
CampusHandai Byoin Mae
Ibaraki-Shi

IbarakiMinamiIbaraki

Shin-Osaka
Awaji

Nakanoshima

Tenjimbashisuji
6-chomeOsaka(Umeda)Kitahama Kyobashi
Yodo

Temma

Nakanoshima yabashi bashi
Namba
CenterKansaiInternational Airport
TennojiTengachaya

Tsuruhashi

JR Shinkansen
JR Lines
SubwaySubway(mido-suji)
Kita-Osaka Kyuko Line
Osaka Monorail
Hankyu Lines
Other Private Lines
Bus Lines

and Industrial Research
9 Osaka University Dental HospitalTrain
12-minute walk from “Kita-Senri” Station
on Hankyu Senri Line.

Saito-nishi

Shibahara Senri-Chuo Yamada

Juso

78

to find our mor

Kadoma-shi

Monorail
20-minute walk from “Handai Byoin Mae” Station
on Osaka Monorail Saito Line.

[How to donate]

nsfer
Credit card, Bank tra
eck the website
For detail please cha-u.ac.jp/english/
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Please make yocilities>d<Institutes an Fa
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De
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■ResearBus・From Senri-Chuo Station :5-minute walk from “Handai-Guchi” Bus Stop on Hankyu
Buses heading to “Onohara Higashi” , “Toyokawa-Eki” ,“Fujikasai” .
12-minute walk from “Handai Honbu Mae” Bus Stop on
Hankyu Buses heading to “Handai Honbu Mae” or“Ibaraki Mihogaoka” .

・From Hankyu Ibaraki-shi Station:

12-minute walk from “Handai Honbu Mae” Bus Stopon buses heading to “Handai Honbu Mae”
(via JR Ibaraki Station).

79