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

2018-2019

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/

2018-2019

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.

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Message from the Director

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
The RIMD History Museum…………………………………………………………………15

Division of Host Defense……………………………………………………………………16

Department of Molecular Immunology
Department 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
Genome Information Research Center………………………………………… 28

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 ……………………………… 36
Department of Bacterial Infections

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 Molecular Protozoology
Department of Virology
International Research Center for Infectious Diseases…………………… 41

Laboratory of Clinical Research on Infectious Diseases
Laboratory of Emerging Viral Diseases
Pathogenic Microbes Repository Unit
Research Center for Mechanism and Regulation of Aging ………………… 44
Yabumoto Department of Intractable Disease Research …………………… 46

Yoshiharu Matsuura D.V.M., Ph.D.
Director
Research Institute for Microbial Diseases
Osaka University

Research Collaboration Center for Infectious Diseases …………………… 48
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 ………………… 54
Vaccine Creation Project
Mucosal Vaccine Project
Vaccine Dynamics Project
Animal Resource Center for Infectious Diseases…………………………… 58

Ofﬁce for Research Promotion …………………………………………………… 59
Common Research Facilities
About RIMD……………………………………………………… 60…………………………………………………………………………… 62

For Students and Researchers who wants to study in RIMD ……………… 70
Grad Students Studying in RIMD

2………………………………………………… 72

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Special Research
Facilities

Organization
Research Divisions

To overcome infectious diseases

Research Center for Infectious Disease Control

To explore the pathogenesis of microbes

Dept. of

Division of Infectious Disease
Dept. of

Matsuura Lab

Shioda Lab

Dept. ofIida Lab

Molecular Virology

Viral Infections

Horiguchi Lab

Kobayashi Lab

Dept. of

Yamamoto Lab

Experimental Genome Research
Ikawa Lab

Dept. of

Genome Informatics
Daron Lab

Dept. of

Infection Metagenomics
Horii LabTo explore the mechanisms that protect against microbes

Division of Host Defense
Dept. ofDept. of

Network Administration
Ofﬁce

International Research Center for
Infectious Diseases

Immunochemistry

Yamasaki Lab

Next-Generation
Sequencing (NGS)Core Facility

To develop new therapeutic approaches to infectious diseases
Dept. ofMolecular Immunology

Host Defense

Virology

To understand our body system from genetic information

Immunoparasitology

Mimuro Lab

Horii Lab

Genome Information Research Center

Dept. of

Infection Microbiology

Dept. ofDept. ofDept. ofMolecular Bacteriology

Dept. ofMolecular Protozoology

Bacterial Infections

Arase Lab

Lab. of Clinical Research on

Lab. of Pathogen Detection

Kamitani Lab

Nakamura Lab

Infectious Diseases

Research Institute
Osaka University

for Microbial Diseases,

and Identiﬁcation

Pathogenic Microbes
Repository Unit

Lab. of Emerging Viral Diseases
Iwasaki Lab

To explore regulatory mechanisms in cancer cells

Division of Cellular and Molecular Biology
Dept. ofDept. ofMolecular Microbiology

Oncogene Research
Okada Lab

Hara Lab

Dept. of

Signal Transduction
Takakura Lab

Dept. of

Cellular Regulation
Miki Lab

Common Research
Facilities
Central Laboratory for
Biological Hazardous
Microbes

Ofﬁce forResearch Promotion

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Animal Resource Center for
Infectious Diseases

CentralInstrumentation
Laboratory

Radioisotope
Laboratory

Administration
General Affairs Section
Accounting Section
Research Cooperation Section

Research Institute for Microbial

Diseases (RIMD) was

est ablished as a r esear chc en t er f or mic r obiolo g y,immunology and oncology in1934. We have performed

outstanding researches in thesefields and we also contributeextensively to growth in thebasic scienc es in Japanthorough advanced researcha n d t h e de v e l o p m e n t o fhuman resources. Now, we arealso developing new

research fields such as geneengineering, genome

research and always exploring

breakthrough in biologicalscience.

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

Yabumoto Department ofIntractable Disease Research
To 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

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 what kinds of bacterial virulence factors are involvedin them. We hope that we will understand the nature of bacterial
infections by answering these questions.

Department of
Molecular Bacteriology

Professor

Yasuhiko Horiguchi

ProfileDr. 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 since 1990. 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.

To understand the mechanism of infection
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.

Analyzing the structure-function relationshipof bacterial protein toxins.
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.

Publication(1) Ectopic Expression of O Antigen in
Bordetella pertussis by a Novel
Genomic Integration System. Ishigaki
K., et al., mSphere (2018)
3:e00417–17–11.
(2) Protective effects of in vivo-expressed
autotransporters against Bordetella
pertussis infection. Suzuki K., et al.,Microbiology and Immunology (2017)61:371–379.

(3) The bvg-repressed gene brtA, encoding
bioﬁlm-associated surface adhesin, isexpressed during host infection by
Bordetella bronchiseptica. NishikawaS., et al., Microbiology and Immunology(2016) 60:93–105.
(4) Detection of genes expressed in
Bordetella bronchiseptica colonizing
rat trachea by in vivo expressed-tag
immunoprecipitation method. Abe H.,
et al., Microbiology and Immunology(2015) 59:249–261.

(5) Polymorphisms influencing expressionof dermonecrotic toxin in Bordetella
bronchiseptica. Okada K., et al., PLoS
ONE (2015) 10:e0116604.
(6) Horiguchi Y. 2012. Swine Atrophic
Rhinitis Caused by Pasteurella multocida
Toxin and Bordetella Dermonecrotic
Toxin. Horiguchi Y., Curr Topics Mcrobiol
Immunol. (2012) 361:113-29

Staff
Asst. Prof. : Yukihiro Hiramatsu ／ Postdoc. : Noriko Shinoda ／Grad. Student 3

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Division of Infectious Disease

Viruses are simple organisms composed of proteins, nucleic
acids, and, in some cases, lipids. Nevertheless, they interact
with several host factors and ultimately cause disease in
humans. Our laboratory focuses on the molecular mechanisms underlying viral diseases, including human immunodeficiency virus (HIV).

Department ofViral Infections

Antiviral host factors and their application
to a cure for HIV infection
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.

Professor

Tatsuo Shioda

Analysis of HIV-1 genome RNA dimerization
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

ProfileDr. Shioda obtaind his B. Sc. fromthe University of Tokyo in 1982 andhis Ph.D. form the same institution
in 1990. After working at the Instituteof 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.

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.

Publication(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. 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.

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

Staff
Assoc. Prof.：Emi E. Nakayama ／Asst. Prof.：Jun-ichi Sakuragi ／ Undergrad. Student 1

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Division of Infectious Disease

Viruses “know” cells better than human beings and have
evolved to replicate in living cells. We are working to understand the molecular mechanisms underlying the interplay
between viruses and host cells through research on hepatitis
viruses, flaviviruses, and insect viruses.

Department of
Molecular Virology

Professor

Yoshiharu Matsuura

Molecular biology of hepatitis viruses
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.
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

ProfileDr. Matsuura received his PhD from
Hokkaido University in 1986 andworked at Research Institute ofDaiichi Seiyaku Co. Ltd for . He wasappointed Professor in RIMD in
2000 after working at NERC Instituteof 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.

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.

Development of baculoviral vectors
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.

Publication(1) 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.
(2) 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.

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

(5) 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.

Staff
Assoc. Prof. : Yusuke Maeda ／ Assoc.Prof.：Takasuke Fukuhara ／Assoc.Prof.：Toru Okamoto ／ SA. Asst. Prof.：Chikako Ono ／Undergrad. Student 2 ／ Grad. Student 9

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Division of Infectious DiseaseIn our immunoparasitology laboratory, we use the apicomplexan protozoan parasite Toxoplasma gondii as a model for exploring host defense systems and pathogenesis. Our research goal
is to elucidate the molecular mechanisms underlying the interface between the host and pathogen.

Dept. of Immunoparasitology

Professor

Masahiro Yamamoto
ProfileBorn at Kumamoto (1979). Received B. Sc. from the University ofTokyo (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 independentassociate professor (2012) at RIMD
in Osaka University. Appointed current position as a Professor of
RIMD in 2013.

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.

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

Publication(1) Essential role for GABARAP autophagy
proteins in interferon-inducible
GTPase-mediated host defense. Sasai
M., et al., Nat Immunol. (2017) 18(8):899-910.
(2) p62 plays a speciﬁc role ininterferon-γ-induced presentation of a
Toxoplasma vacuolar antigen. Lee Y., etal. Cell Rep. (2015) 13:223-33.

(3) 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.
(4) 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.

(5) Role of the mouse and human
autophagy proteins in IFN-γ-induced
cell-autonomous responses against
Toxoplasma gondii. Ohshima J., et al.
J Immunol. (2014) 192: 3328-35.

Rhoptry(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.

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

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

Staff
Assoc. Prof. ：Miwa Sasai ／ Asst. Prof. : MA JISU ／Postdoc.：Hironori Bando ／ Grad. Student 4

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Division of Infectious Disease

Department of
Infection Microbiology

Bacteria-gut interplay and the host immune response are the mostcritical issues in determining the fate of bacterial infections and theseverity of the diseases. Our group has been studying the pathogenesis of mucosal infectious bacteria, such as Helicobacter pylori, Shigella,enteropathogenic Escherichia coli, and Streptococcus pyogenes, bydefining the molecular and cellular mechanisms of infections and theroles of pathogenic factors as well as the host factors in infections.

Staff

The RIMD History Museum

Asst. Prof.：Ryota Otsubo ／ Postdoc：Takahito Sanada ／The RIMD History Museum, which opened in 2010, is a 70th anniversary memorial project launched by the

Guest Researcher : Phawinee Subsomwong

Research Institute for Microbial Diseases (RIMD). Many historical items related to RIMD are on display. The
museum is open to the public and, as of 2017, has been visited by more than 10,000 people.

Opening Ceremony (December 17th, 2010)

Associate Professor

Hitomi Mimuro

ProfileDr. Mimuro received her Ph.D. from The University ofTokyo in 2004. She became Assistant professor at theInstitute of Medical Science, The University of Tokyo in2005 and worked for the same institution. She was appointed Associate Professor in RIMD in 2017 (also holda post in The University of Tokyo).

Present at the Ceremony were Dr. Hitoshi Kikutani (the then Director of RIMD; middle in the photo), Dr.
Higashi Yasushi (the then Director General of BIKEN foundation; left in the photo), and Mr. Tokuharu Takeo(a descendant of Jiemon Takeo, who contributed to the Takeo Research Institute, which merged with RIMD
in 1934; right in the photo).

Publication(1) Epigenetic silencing of miR-210 increases theproliferation of gastric epithelium during chronic
Helicobacter pylori infection. Kiga K., et al. Nat Commun.
(2014) Sep 4;5:4497.
(2) The immune receptor NOD1 and kinase RIP2 interact withbacterial peptidoglycan on early endosomes to promote
autophagy and inflammatory signaling. Irving AT., et al.
Cell Host Microbe. (2014) May 14;15(5):623-35.
(3) Shigella IpaH7.8 E3 ubiquitin ligase targets glomulin andactivates inflammasomes to demolish macrophages.
Suzuki S., et al. Proc Natl Acad Sci U S A. (2014) Oct 7;111(40):E4254-63.

Inside Museum(4) BabA-mediated adherence is a potentiator of the
Helicobacter pylori type IV secretion system activity.
Ishijima N., et al. J Biol Chem. (2011) Jul 15;286.

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
host epithelial 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.

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RIMD Chronology and Koch’ s Microscope

Samples shown by Microscope

Location：RIMD Main Building 1F
Open：9:00–17:00 Weekdays
Free of charge
http://www.biken.osaka-u.ac.jp/museum/

Research History at RIMD

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Division of Host Defense

Department of
Molecular Immunology

Our bodies are continuously exposed to external and internal insults caused by infection andtissue damage, most of which are primarily sensed by immune receptors to maintain tissue
homeostasis. However, the molecular mechanism by which these 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 clustered C-type lectin receptors, Mincle, MCL, Dectin-2 and DCAR, canrecognize mycobacteria through their unique glycolipids possessing adjuvant activity (Figure2). Our objective is to illustrate the principle behind the regulation of immune responses throughC-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.

Professor

Sho Yamasaki

ProfileDr. Yamasaki received his Ph.D.
from Kyoto University in 1999.
After working at Mitsubishi Chemical Corporation and Chiba University Graduate School of Medicine, heworked for Research Center for Allergy and Immunology, RIKEN from2004 to 2009. He was appointed as
Professor in Medical Institute of
Bioregulation, Kyushu University in2009. He took his current position
at RIMD from 2017.

C-type lectin receptors (CLRs) sense both“non-self pathogens” and “damaged self”.

Self ligands are recognized
by T cell receptors (TCRs) andplay an important role in T cell persistence

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].

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.

Fig.1 Various immune responses triggered by Mincle

Fig.2 Cooperative function of CLRs against mycobacteria

Novel T cell subsets contributeto autoimmune diseases
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.

Publication(1) 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.

(3) 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.

(2) Dectin-2 is a direct receptor for
mannose-capped lipoarabinomannanof mycobacteria. Yonekawa A., et al.
Immunity. (2014) 41:402-13.

(4) Direct recognition of the mycobacterial
glycolipid, trehalose dimycolate, by
C-type lectin Mincle. Ishikawa E., et al.
J. Exp. Med. (2009)206:2879-88.

(5) Mincle is an ITAM-coupled activating
receptor that senses damaged cells.
Yamasaki S., et al. Nat. Immunol.
(2008)9:1179-88.
(6) Mechanistic basis of pre-T cell
receptor-mediated autonomous
signaling critical for thymocyte
development. Yamasaki S., et al. Nat.
Immunol. (2006)7:67-75.

Staff
Asst. Prof.：Eri Ishikawa ／ Asst. Prof.：Chihiro Motozono ／Postdoc.：Masahiro Nagata ／ Guest Researcher : Daiki Mori ／Grad. Student 12

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17

Division of Host Defense

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

Dept of Immunochemistry

Professor

Hisashi Arase (concur.)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).

ProfileProf. 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 Institutefor Microbial Diseases (2004). he isworking as current position from
2006.

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.

Publication(1) Immune evasion of Plasmodium
falciparum by RIFIN via inhibitory
receptors. Saito F et al. Nature (2017)
552:101–105.
(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.

(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.

Staff

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).

Fig. 3. Misfolded proteins complexed with MHC class II molecules
are targets 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).

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

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19

Division of Cellular andMolecular Biology

Department of
Molecular Microbiology

It has become apparent that aging has a major impact on theincidence of cancers. However, the underlying mechanisms areunclear. We think that cellular senescence plays a key role. In ourlaboratory, we are aiming to understand the roles and mechanismsof cellular senescence in vivo. We believe that understanding themolecular mechanisms underlying cellular senescence in vivo will
provide valuable insight into the development of aging-associateddiseases such as cancer, and open up new possibilities for theircontrol.

Professor

Eiji Hara

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.

ProfileDr. 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 Institute for Genome
Research, University of Tokushima(Professor), he was appointed Division Chief in the Cancer Institute,Japanese Foundation for Cancer Research in 2008. He took his current
position at RIMD from 2015.

Publication(1) Ablation of the p16INK4a tumour
suppressor reverses ageing
phenotypes of klotho mice. Sato S., etal. Nature Communications (2015)
6:7035.

(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.

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

20

Understanding the molecular mechanisms
underlying inflammatory diseases induced
by senescence-associated secretory
phenotypes (SASPs)

Exploring the physiological roles andmechanisms underlying cellular senescencein vivo

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.

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.

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 andMolecular Biology

Cancer develops due to accumulation of mutations within a cell,which can then become malignant through immortalization andtransformation. The malignant traits of cancer cells occur as
they evade cancer inhibitory mechanisms such as 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.

Department of
Oncogene Research

Professor

Masato Okada
ProfileThe molecular mechanism underlying
p18/Ragulator and mTOR nutrient signaling

Src and cancer development
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 anactivator of signaling pathways that control remodeling of thecytoskeleton, which contributes to motility by inducing morphological changes. In addition, Src is involved in cell membrane-mediated signaling pathways that promote expressionof genes encoding proteases, thereby leading to malignancy.
We aim to further elucidate the detailed molecular mechanisms by which Src affects cancer cell invasion and metastasis.
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 compete witheach 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.

Dr. Okada graduated Kyoto University School of Science in 1981 andreceived his Ph.D. from Osaka University in 1988. He worked as a Research Associate at the Institutefor Protein Research in Osaka University and became an Associate
professor in 1996 in the same institution. He was appointed current
position as a Professor of RIMD in
2000.

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 unique inthat they have an exceptionally long life span (up to 10 times
that of mice). They also exhibit significant resistance to aging
and cancer. Our laboratory focuses on identifying the molecular mechanisms that allow NMR to acquire these traits.

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

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: e258(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

Staff
Assoc. Prof.：Shigeyuki Nada ／ Assoc. Prof.：Norikazu Yabuta ／Asst. Prof.：Kentaro Kajiwara ／ Postdoc.：Akira Ogawa ／Undergrad. Student 3 ／ Grad. Student 10

22

Fig2. Protein Structure for Ragulator complex
23

Division of Cellular andMolecular Biology

Tissue-specific stem cells continuously produce terminally differentiated functional cells and maintain organ integrity. Bloodvessels supply oxygen and nutrients to all tissues; tissues andorgans cannot develop without blood vessel formation. Our aim
is to elucidate the cellular and molecular mechanisms underlying
vascular formation (particularly those involving stem cells) andto develop strategies to manage patients with vascular diseases.

Department of
Signal Transduction

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 alignment isregulated by the apelin/APJ system and is critical forthermoregulation (Kidoya, Dev Cell 2015).

Stemness and vascular niche

Professor

Nobuyuki Takakura

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 developing

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

E 14.5

Publication(1) CD157 Marks Tissue-Resident Endothelial
Stem Cells with Homeostatic andRegenerative Properties. Wakabayashi T,
Naito H, Suehiro JI, Lin Y, Kawaji H, Iba T,
Kouno T, Ishikawa-Kato S, Furuno M,
Takara K, Muramatsu F, Weizhen J,
Kidoya H, Ishihara K, Hayashizaki Y,
Nishida K, Yoder MC, Takakura N. Cell
Stem Cell 22(3):384-397, 2018.
(2) APJ Regulates Parallel Juxtapositional
Alignment of Arteries and Veins in theskin. Kidoya H., et al. Dev Cell (2015) 33(3):247-59.

(3) Identiﬁcation and characterization of aresident vascular stem/progenitor cell
population in preexisting blood vessels.
Naito H., et al. EMBO J (2012) 31(4):842-55.
(4) Spatial and temporal role of theapelin/APJ system in the caliber size
regulation of blood vessels during
angiogenesis. Kidoya H., et al. EMBO J(2008) 27(3):522-34.

(5) A role for hematopoietic stem cells inpromoting angiogenesis. Takakura N.,
et al. Cell (2000) 102(2):199-209.

Asst. Prof.：Hiroyasu Kidoya ／ Asst. Prof.：Hisamichi Naito ／Postdoc.：Jia Wei Zhen ／ Postdoc.：Fumitaka Muramatsu

E 15.0in 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 withintumors.

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 toanti-angiogenic therapy (Naito, Cancer Res 2016). We are
examining how endothelial stem cells develop and how they
are maintained during development with a view to using thiscell population to treat vascular disease.

E 15.0Fig. 1. Vascular development in mouse embryos. Hierarchal architecture of blood vessels accompanied by arterial (yellow)–venous(blue) alignment. Green; endothelial cells.

(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.

Staff

24

Mechanism of vascular formation

initiation

Fig. 2. Endothelial cells (blue) andCSCs (green) in a tumor.
CSCs localize at the perivasculararea, the so called “vascular niche.”repairedFig3. 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 andMolecular Biology

Most cancers originate from epithelial cells. Normal epithelial
cells form a sheet-like tissue structure in which cells are tightly
attached to each other and to the 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 the mechanism underlying thismysterious process of cancer development.

Department of
Cellular Regulation

Professor

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

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 eachother and collectively maintain their structure; these characteristics are disrupted in cancer tissues. Forced expressionof 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.

Publication(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.

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

26

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).

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

27

Genome Information Research Center

Department of Experimental
Genome Research

In the past, animals harboring natural mutations have beenused to elucidate the mechanisms underlying various diseases.
In the “post-genome project era,” genetically modified animals
play a key role in basic molecular biological investigations andact as models of human disease. Our laboratory studies themechanisms underlying mammalian reproductive systems
through genetic manipulation of animal models.

Professor

Masahito Ikawa (concur.)Analysis of molecular mechanisms involvedin mammalian gametogenesis, fertilization,and implantation
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 project.
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.

Development of new technologies for
producing genetically modified animals

ProfileDr. Ikawa received his Ph.D. from
Osaka University in 1997. After working as JSPS postdoctoral fellow anda 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 toOsaka University in 2002, he becamean Associate Professor in 2004 andwas 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.

Another tool improved by work in our laboratory is lentiviral(LV) vector-mediated genetic manipulation in vivo. We devel-

Publication(1) Sperm-borne phospholipase Czeta-1
ensures monospermic fertilization in
mice. Nozawa K., et. Al., (2018) Sci Rep.
8(1):1315.

(3) CRISPR/Cas9 mediated genome
editing in ES cells and its application
for chimeric analysis in mice. Oji A., etal. Sci Rep. (2016) 6:31666.

(2) 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.

oped 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).

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.

(6) Sperm calcineurin inhibition prevents
mouse fertility with implications formale contraceptive. Miyata H., et al.
Science. (2015) 350(6259):442-5.

Staff
Assoc. Prof.：Yuhkoh Satouh (concur.) ／ Asst. Prof.：Yoshitaka Fujihara ／ Asst. Prof.：Haruhiko Miyata ／Asst. Prof.：Taichi Noda ／ SA Asst. Prof.：Daiji Kiyozumi (concur.) ／ Asst. Prof.：Tsutomu Endo (concur.) ／Asst. Prof.：Julio Manuel Castaneda ／ Postdoc. : Keisuke Shimada ／ Postdoc：Lu Yonggang ／Postdoc. : Nobuyuki Sakurai ／ Guest Professor：Martin M. Matzuk ／ Guest Researcher : Masaru Okabe ／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)

Undergrad. Student 5 ／ Grad. Student 5
28

29

Genome Information Research CenterWe are a bioinformatics laboratory, which means that we use
computational methods to study problems that are difficult or
impossible to investigate experimentally. Some of the problems
we work on include: analysis of B and T cell receptor repertoires,protein-nucleotide interactions and multiple sequence alignmentof protein and nucleotide sequences. These themes aredescribed in more detail below.

Department of
Genome Informatics

Professor

B and T cell receptor repertoires

A healthy immune system maintains a vast repertoire of
B and T cells that can recognize a wide range of molecules. Functional analysis of B and T cell receptor
sequences has the potential to reveal not only biomarkers for disease but also therapeutic compounds. Indeed,
immune-based therapies, primarily based on engineered
B cell receptors, are now the fastest-growing area inpharma. We are developing bioinformatics methods tomine immune receptor sequence data in order to accelerate discovery of novel therapeutic compounds.

Daron M. Standley

Protein-nucleotide interactions

Protein-nucleotide interactions play a central role in the flowof 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. Morerecently, the importance of RNA-binding proteins (RBPs) inmaintenance of homeostasis as well as in shaping thestrength and duration of immune responses post-transcriptionally has been noted. In order to gain further insight into themechanisms of RBP-mediated immune regulation, we aredeveloping tools for nucleotide binding site prediction andflexible protein-nucleotide docking.

Multiple sequence alignment

ProfileProf. Standley received his PhD in
Chemistry from Columbia University
in 1998. He then joined Schrodinger,
Inc. where he worked as a scientificsoftware developer for five years. In
2003 he moved to the Institute forProtein Research, Osaka University
as a Senior Scientist. He joined the
Immunology Frontier Research Institute (IFReC) as a Principal Investigator in 2008 and, after a two-yearcross-appointment at Kyoto University’s Institute for Virus Research,
became a Professor full time at the
Research Institute for Microbial Diseases in 2016.

Multiple sequence alignment (MSA) is an important stepin many comparative analyses of biological sequences
and MAFFT is one of the most popular programs forbuilding MSAs. Since the first release of MAFFT in 2002,
we have been continuously improving its accuracy,
speed and utility in practical situations, and have provided different options for newly emerging types of data andanalyses. Recent features include: inclusion of secondary structural information of non-coding RNAs andproteins, interactive selection of sequences for phylogenetic tree inference, etc. We are working on an extension to make more accurate options applicable to a larger
number of sequences, responding to the demands oflarge-scale analyses.

Publication(1) Kotai Antibody Builder: automatedhigh-resolution structural modeling ofantibodies. Yamashita, K. et al.
Bioinformatics 30, 3279-3280 (2014).

(3) Malt1-induced cleavage of regnase-1 in
CD4(+) helper T cells regulates
immune activation.Uehata, T. et al. Cell
153, 1036-1049 (2013).

(2) Quantifying sequence and structuralfeatures of protein-RNA interactions.
Li, S., Yamashita, K., Amada, K. M. &Standley, D. M. Nucleic Acids Res 42,
10086-10098 (2014).

(4) MAFFT multiple sequence alignment
software version 7: improvements inperformance and usability. Katoh, K. &Standley, D. M. Mol Biol Evol 30,
772-780 (2013).

(5) SeSAW: balancing sequence andstructural information in proteinfunctional mapping. Standley, D. M.,
Yamashita, R., Kinjo, A. R., Toh, H. &Nakamura, H. Bioinformatics 26,
1258-1259 (2010).
(6) Zc3h12a is an RNase essential forcontrolling immune responses byregulating mRNA decay. Matsushita, K.
et al. Nature 458, 1185-1190 (2009).

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

30

31

Genome Information Research Center

Department of
Infection Metagenomics

Next-generation sequencing (NGS) is a technology that cangenerate enormous amount of genomic information in ashort time and has made huge progress in genomic scienceand infectious 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.

Head
Professor

Toshihiro Horii (concur.)Professor

Tetsuya Iida (concur.)

Development of methods for pathogen
detection based on metagenomic analysis
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.

Genomic analysis of microbial pathogens
MinION

HiSeq2500

HiSeq3000

Study of gut flora during onset of
infectious disease
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.

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.

MiSeq

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.

(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.

(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.

(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.

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

Fig. 2.

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

32

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.

33

Genome Information Research Center

Genome Information Research Center

Laboratory of Genome Research
Next-Generation Sequencing (NGS)Core Facility

Staff
Prof. (concur.) : Tetsuya Iida, Ph.D.
SA Assoc. Prof. (concur.) : Shota Nakamura, 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 fromNGS and DNA microarrays by combining bioinformatics
approaches with large computing systems designed for big
data. Recently, we have begun supporting activities outside of
infectious disease research for researchers from Osaka
University as well as other universities.

Associate Professor

ProfileTakeshi Miwa

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 of Tokyo andStanford University.

Asst. Prof. : Daisuke Okuzaki, Ph.D.
SA Asst. Prof. (concur.) : Daisuke Motooka, Ph.D.

Publication
Advanced NGS Instruments
In the last decade, as a result of the remarkable technological innovation 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 IonPGM (LifeTechnologies), MiSeq, HiSeq (Illumina), and PacBio RSII
(Pacific Biosciences) are available in our Core Facility. We
provide genomics applications according to researchers’
needs in addition to training courses covering topics such as
NGS procedures as well as other related experimental
technologies. Furthermore, we are expanding research withthe aim of improving bioinformatics analysis in collaboration
with the Department of Genome Informatics and the Department of Infection Metagenomics.

Publication(1) 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.
(2) Quasispecies of Hepatitis C Virus Participate in Cell-Speciﬁc
Infectivity. Fukuhara T., et al. Sci Rep. (2017) Mar 22;7:45228.
(3) Polarization of M2 macrophages requires Lamtor1 that
integrates cytokine and amino-acid signals. Kimura T., et al.
Nat Commun. (2016) Oct 12;7:13130.
(4) Microarray and whole-exome sequencing analysis of familial
Behçet's disease patients. Okuzaki D., Sci Rep. (2016) Jan
20;6:19456.

34(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(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(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

We are currently using animal models to investigate the molecularbiological mechanisms involved in human disease, particularly cardiovascular disease.

Next Generation Sequencer HiSeq

Large-scale computer system for NGS(1) Connexin45 contributes to global cardiovasculardevelopment by establishing myocardial impulse
propagation. Nishii K., et al. Mech Dev. (2016) 140:41-52

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 ofhypertensive HFpEF and also regulate the effect of carnitine when administered 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 manytissues 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.

35Research Center for Infectious
Disease Control
In our laboratory, we are conducting research and collecting genomic
information to understand how bacterial pathogens infect the host andcause disease. In addition, by developing new pathogen detection
methods using high-throughput DNA sequencers, we aim to identify
novel pathogens and reveal the pathogenesis of unknown infectious
diseases.

Department ofBacterial Infections

Professor

Tetsuya Iida

ProfileDr. Iida graduated Faculty of Science, Kyoto University in 1984 andreceived his Ph.D. from Osaka university in 1991. He was appointed
SA Professor at the International
Research Center for Infectious Diseases in RIMD after working as a
Research Associate for six years
and an Associate Professor forseven years. He took his current position as a Professor of RIMD in2015.

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.

Development of methods to diagnosebacterial infections based on genomics
and metagenomics
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 agents that causesuch infections, and to understand the underlying pathogenesis, we are developing a high-throughput DNA sequencing-based system to detect pathogens and analyze theirvirulence traits.

Fig. 1. The genomes of bacteria belonging to genus Vibrio
comprise two distinct circularchromosomes.

Publication(1) 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.

(3) 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.

(2) 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) 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.

Staff
Assoc. Prof.：Toshio Kodama ／Asst. Prof.：Shigeaki Matsuda ／ Grad. Student 5

36

Identifying the mechanism(s) underlying
bacterial infection and pathogenesis(5) Metagenomic diagnosis of bacterial
infections. Nakamura S., et al. Emerg
Infect Dis. (2008) 14(11):1784-6.
(6) Genome sequence of Vibrio
parahaemolyticus: a pathogenic
mechanism distinct from that of V
cholerae. Makino K., et al. Lancet.
(2003) 361(9359):743-9.

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.

37

Research Center for Infectious
Disease Control

Department of
Molecular Protozoology

Malaria is widespread in tropical and subtropical regions,and millions of people, particularly in Africa, remain at riskof disease and death despite substantial progress inmalaria control. No effective malaria vaccine has beendeveloped or licensed. Our laboratory is undertaking basic
research and conducting clinical trials on our own candidate vaccine antigen gene.

Professor

Toshihiro Horii

ProfileDr. Horii received his Ph.D. from
Osaka University in 1981. After
working at the Faculty of Sciencein Osaka University as Research
Associate, he was appointed Associate Professor at RIMD in 1991
and became Professor in 1999.

(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.

(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.

Molecular strategy for parasite survival
and a function of SE36 molecule
The malaria parasite develops highly sophisticated strategies to evade the human immune system. One of the mostdifficult phenomena encountered by those developing vaccines
is genetic polymorphism of vaccine candidate genes; that is,field-isolated parasites harbor different sequences from thevaccine candidate genes. Fortunately, SERA5 is highly homologous among malaria parasites worldwide. We haveanalyzed protective epitopes on SE36 molecule. Recently wehave shown that SE36 tightly binds to host vitronectin on thesurface of parasite cell, merozoite, and vitronectin further
binds to over 30 different host proteins for molecular camouflage from host immune system.

(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.

Staff
Prof.：Palacpac Nirianne Marie Querijero ／Asst. Prof.：Nobuko Arisue ／ Asst. Prof.：Takahiro Tougan ／Postdoc.：Edula Jyotheeswara Reddy ／38

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 (the malaria parasite) and developed malaria
vaccine BK-SE36 by utilizing a recombinant SERA5 protein.
SERA5 is a protein that is highly expressed/produced inlarge 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/clinical malaria, albeit suchchildren 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 trials in Burkina Faso West Africa involving
toddlers aged 1 - 5 years to evaluate safety. Currently we areconducting further clinical trials with a new formulation containing CpG adjuvant that stimulate innate immunity.

Fig. 1. Clinical trial of the BK-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.

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.

Malaria vaccine targeting SERA5

Fig. 2.
Kaplan-Meier curves for 6- to 20-year-olds at 130–365
days post-second vaccination with BK-SE36.
Comparison of the number of days from 130-365 days
after second vaccination that 6-20 year-old BK-SE36
vaccinees and control grouped developed clinical malaria.

39

Research Center for Infectious Disease Control

Staff

Department of Virology

Staff

Assis. Prof.：Yuta Kanai ／SA Assis. Prof.：Akatsuki Saito ／Postdoc.：Takahiro Kawagishi ／Postdoc.：Yutaka Terada ／Grad. Student 2

Grad. Student 1

Associate Professor

Takeshi Kobayashi

International Research Center for
Infectious Diseases

Laboratory of Clinical Researchon Infectious Diseases

SA Associate Professor

ProfileProfileDr. 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 toJapan to work at the Institute for Virus Research in Kyoto
University. He was appointed SA Associate Professor of
RIMD in 2012. He is in his current position from 2016.

Dr. Kamitani received his Ph.D. from Osaka University in
2003. After working at RIMD for one year, he spent theperiod 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(1) Lethal murine infection model for human respiratory
disease-associated Pteropine orthoreovirus. Kanai Y., et al.,
Virology (2018) 514:57-65.
(2) Entirely plasmid-based reverse genetics system forrotaviruses. Kanai Y, Komoto S, Kawagishi T, Nouda R,
Nagasawa N, Onishi M, Matsuura Y, Taniguchi K, Kobayashi
T. Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):2349-2354.
(3) 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.

Wataru Kamitani

Publication(1) MERS coronavirus nsp1 participates in an efﬁcient
propagation through a speciﬁc interaction with viral RNA.
Terada Y., et al. Virology. (2017) 511:95-105.
(2) Two-amino acids change in the nsp4 of SARS
coronavirus abolishes viral replication. Sakai Y., et al.
Virology. (2017 ) 510:165-174.
(3) Severe Acute Respiratory Syndrome Coronavirus nsp1
Facilitates Efﬁcient Propagation in Cells through aSpeciﬁc Translational Shutoff of Host mRNA. Tanaka T.,
et al. J. Virol. (2012) 86(20):11128-37(4) Rapid whole genome sequencing of Miyazaki-Bali/2007
Pteropine orthoreovirus by modiﬁed rolling circular
ampliﬁcation with adaptor ligation - next generation
sequencing. Singh H., et al. (2015) Sci. Rep. 5:16517.

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 cellswith an activated Ras signaling pathway. Wild-type

40

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

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 coronaviruses. Our group try to understand the mechanism of Coronavi-

ruses 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

Laboratory of
Emerging Viral Diseases

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

SA Associate Professor

Masaharu Iwasaki

ProfileDr. 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 SeniorResearch Associate (2015), and a Staff Scientist (2017) at
The Scripps Research Institute, where he studied the molecular mechanisms underlying mammarenavirus multiplication. He was appointed to his current position in 2018.

International Research Center for
Infectious Diseases

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.

Pathogenic Microbes
Repository Unit

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

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.
(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.

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-42

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.

Fig. (A) Schematic diagram of the genome organization of
mammarenaviruses. (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 Regulation of Aging

Staff
Director : Eiji Hara

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.

Associate Professor

ProfileMasami Nozaki

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 the same institution.

Publication(1) Lapatinib-resistant cancer cells possessing epithelial
cancer stem cell properties develop sensitivity during
sphere formation by activation of the ErbB/AKT/cyclin D2
pathway. Ohnishi Y., et al. Oncol Rep (2016) 36 (5):3058-64.
(2) Cetuximab-resistant oral squamous cell carcinoma cells
become sensitive in anchorage-independent culture
conditions through the activation of the EGFR/AKT
pathway. Ohnishi Y., et al. Int J Oncol.(2015) 47(6):2165-72.
(3) Interaction between basigin and monocarboxylatetransporter 2 in the mouse testes and spermatozoa. ChenC., et al. Asian J Androl (2016) 18 (4):600-6.
(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.

■ 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: Invited Professor Toru Ishitani
Lab of Integrated Signaling Systems, Institute for
Molecular & Cellular Regulation, Gunma 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
Biomedical Animal Research Laboratory,
Intsitute for Genetic Medicine, Hokkaido 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

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 disease difficult
to treat. Thus, our aim is to understand the characteristics ofcancer stem cells and establish new treatment strategies.

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

45

Yabumoto Department of Intractable Disease Research
How are GPI-anchored proteins(GPI-APs) regulated?
Glycosylphosphatidylinositol (GPI) is a glycolipid attached to proteins
and anchors them onto the plasma 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 toelucidate biogenesis, transport and remodeling of GPI-anchoredproteins and understand its physiological significance in our body.

Endowed Chair Professor

Endowed Chair Professor

Taroh Kinoshita

Yoshiko Murakami

ProfileProfileDr. 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, he appointed 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.

Dr. Murakami received Ph.D. from Osaka University in 2001.
After working at Osaka University Hospital and Hyogo 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.

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.

Molecular mechanisms of GPI deficiencies.
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.

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.

(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.

(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.

(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.

Staff
Grad. Student 1

46

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

47

Thailand-Japan Research Collaboration Center
Section of Bacterial Infections

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).”

In 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.

Thailand-Japan Research
Collaboration Center

SA Professor

Kazuhisa Okada Profile
Dr. Okada received his Ph.D. from Osaka university in2005 and joined RIMD as a postdoctoral fellow in thatsame year. He was appointed Lecturer of Thailand-Japan Research Collaboration Center on Emerging andRe-emerging infections in 2015 after working as a Postdoctoral fellow from 2005 to 2011 and an Asistant Professor from 2011 to 2015 in the same institution.

Shigeyuki Hamada (concur.)
SA Associate Professor

Kazuhisa Okada

Publication(1) Vibrio cholerae embraces two major evolutionary traits asrevealed by targeted gene sequencing. Okada K., et al. Sci.
Rep. (2018) 8(1):1631(2) Characterization of 3 Megabase-Sized Circular Replicons
from Vibrio cholerae. Okada K., et al. Emerg Infect Dis.
(2015) 21(7):1262-3.
(3) Cholera in Yangon, Myanmar, 2012-2013. Aung WW., et al.
Emerg Infect Dis. (2015) 21(3):543-4.
(4) Vibrio cholerae O1 isolate with novel genetic background,
Thailand–Myanmar. Okada K., et al. Emerg Infect Dis.
(2013) 19:1015-7.

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

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

48

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.
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.

49

Thailand-Japan Research
Collaboration Center
Section of Viral Infections

Staff

Staff

SA Assoc. Prof.：Atsushi Tanaka ／Assoc. Prof.：Yukihiro Akeda (concur.) ／SA Assoc. Prof.：Hiroto Mizushima

SA Professor

Masashi Tatsumi

ProfileDr. Tatsumi received his Ph.D. from The University ofTokyo. After working at National Institute of Health inJapan, Pasteur Institute and INSERM (French National
Institute of Health and Medical Research) in France, hespent 12 years in National Institute of Infectious Diseases. After retirement, he served as a chief advisor for JICA
until taking his current position at RIMD in 2016.

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(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.
(3) Evolutionary constraints on the norovirus pandemic
variant GII.4_2006b over the ﬁve-year persistence inJapan. Sato H et al Frontiers in Microbiology 2017 8:410

SA Asst. Prof.：Yo Sugahara ／SA Researcher : Noriko Sakamoto

Thailand-Japan Research
Collaboration Center
Section of Bacterial Drug
Resistance Research

ProfileSA Professor

Shigeyuki Hamada

Dr. Hamada received D.D.S. and Ph.D. degrees from Osaka
university in 1967 and 1971, respectively. He joined thesame university as an Assistant Professor from 1977 andan Associate Professor in 1977. He became the Directorof Dental Research, National Institute of Health in 1980.
He was appointed to current position in 2009 after working as Professor of Microbiology in Osaka University
School of Dentistry from 1986 to 2005 and a Professorof Nihon University Advanced Research Institute for the
Sciences and Humanities from 2005 to 2009.

Publication(1) Genetic characterization of blaNDM-harboring plasmids
in carbapenem-resistant Escherichia coli from Myanmar.
Sugawara Y., et al., PLOS ONE (2017)12 (9): e0184720.
(2) PCR-Dipstick chromatography for differential detection of
carbapenemase genes directly in stool specimens.
Shanmugakani, R.K., et al. Antimicrob Agents Chemother.
(2017) 61(6): e00067-17(3) Fetal septic meningitis in child caused by Streptococcus
suis serotype 24. Kerdsin, A., et al. Emerg. Infect. Dis.
(2016) 22(8): 1519-1520.
(4) Molecular and genomic characterization of pathogenic
traits of group A Streptococcus pyogenes. Hamada S., etal. Proc. Jpn Acad. Sci. (2015) B91: 539-559.

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 their

50

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.

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 public healthcommunities worldwide. Japan is no exception, even though
the prevalence of CRE at this time remains low. Our aim is to
examine the epidemiological dissemination of CRE in theSoutheast Asian countries. Carbapenem resistance is usually
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 toleading hospitals in Thailand and Myanmar. CRE isolates are
identified by biochemical characterization or MALDI-TOF-MS,
followed by profiling using pulsed-field gel electrophoresis(PFGE) and multilocus sequence typing (MLST). We thendetermine the whole genome sequence of CRE isolates to
identify the full plasmid and construct a comprehensive imageof the relationships between isolates based on MLST andphylogeny. By undertaking these genomic epidemiologicalstudies, we increase our understanding of how CRE spreadand 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.

51

Thailand-Japan Research
Collaboration Center

Thailand-Japan Research
Collaboration Center

Staff
SA Asst. Prof.：Akatsuki Saito (concur.)

Section of Antiviral Research

Professor

Tatsuo Shioda (concur.)

ProfileDr. Shioda obtaind his B. Sc. from the University of Tokyoin 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.

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.

Mahidol-Osaka Center for
Infectious Diseases

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

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

Publication(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.

(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.

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.

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

Diagnostic kit developed by the MOCID.

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.

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

52

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

53BIKEN Innovative Vaccine Research
Alliance Laboratories

Staff

Postdoc.：Kazuki Misato ／Undergrad. Student 4 ／Grad. Student 3

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

Staff
Vaccine Creation Project

ProfileDirector, SA Professor

Koichi Yamanishi

SA Associate Professor

Yasuo Yoshioka

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 Sciencesin Osaka University.

Publication(1) 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.
(2) Metal nanoparticles in the presence oflipopolysaccharides trigger the onset of metal allergy inmice. Hirai T, Yoshioka Y, et al. Nat Nanotechnol. (2016) 11(9):808-16.
(3) Silica and titanium dioxide nanoparticles cause
pregnancy complications in mice. Yamashita K, Yoshioka
Y, et al. Nat Nanotechnol. (2011) 6(5):321-8.
(4) Interleukin-1 family cytokines as mucosal vaccine
adjuvants for induction of protective immunity against
influenza virus. Kayamuro H, Yoshioka Y, et al. J Virol.
(2010) 84(24):12703-12.

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

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.

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

54

55

BIKEN Innovative Vaccine Research
Alliance Laboratories

BIKEN Innovative Vaccine Research
Alliance Laboratories

Staff
Mucosal Vaccine Project

Grad. Student 1

Staff
Postdoc：Yasunari Haseda

Vaccine Dynamics Project

SA Associate Professor

Shintaro Sato

SA Associate Professor

ProfileProfileDr. 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 and at University ofTokyo as an Assistant 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 in2015 after working at Washington University in St. Louis,
NIBIOHN, and IFReC in Osaka University.

Publication

Publication(1) A Reﬁned Culture System for Human Induced Pluripotent
Stem Cell-Derived Intestinal Epithelial Organoids.
Takahashi Y., et al. Stem Cell Rep. (2018) 10(1):314.

(1) Quantifying the relative immune cell activation fromwhole tissue/organ-derived differentially expressed genedata. Wijaya E., et al. Sci Rep. (2017) 7(1):12847.

(2) Allograft inflammatory factor 1 is a regulator oftranscytosis in M cells. Kishikawa S., et al. Nat. Commun.
(2017) 8:14509.

(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.

(3) Innate lymphoid cells regulate intestinal epithelial cell
glycosylation. Goto Y., et al. Science (2014) 345(6202):1254009.
(4) Transcription factor Spi-B-dependent and -independent
pathways for the development of Peyer's patch M cells.
Sato S., et al. Mucosal Immunol. (2013) 6(4):838-46.

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.

56

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

57

Animal Resource Center for Infectious Diseases

Office for Research Promotion

Staff
Head, Prof. : Masahito Ikawa
Assoc. Prof. : Yuhkoh Satouh
Asst. Prof. (concur.) : Yoshitaka Fujihara
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.

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

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.

Staff

The office provides the following services:
1. Management of International Forums:
Table 1 *Tg, Transgenic; KO, Knockout; IVF, in vitro
Fertilization; ET, Embryo transfer.

Head, Prof. (concur.) : Masato Okada

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

Assoc. Prof. : Ryo Iwamoto
SA Asst. Prof. : Saya Nakagomi

2. Organizes seminars and lectures at RIMD.

IVF/ETTG

KO, KI

-2000

261

228

50

2001-2003

443

104

57

4. Organizes orientation and Lab Tours for RIMD and IFReC for
candidates looking to fill graduate school/post-doctoral positions.

2004-2006

331

43

69

5. Analyzes institutional research activity and performance.

2007-2009

216

22

74

2010-2012

388

55

152

2013-2015

580

50

242*

3. Organizes Lecture Programs for undergraduate and graduate
students.

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.

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.

58

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 students

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).

59

Common Research Facilities

Common Research Facilities

Central Instrumentation
Laboratory

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

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.
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.

General Affairs Section
Accounting Section
Research Cooperation Section

Central Laboratory for Biological
Hazardous Microbes

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

Administration

Central Instrumentation Laboratory staffs

Radioisotope Labolatory

Staff
Head, Prof. (concur.) :Hiroaki Miki60

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.

61

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).

2000 年頃

1970 年頃

1980 年頃

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

1950 年頃

Discovered Vibrio parahaemolyticus

Tsunesaburo Fujino

1960 年頃
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 disease

62

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

63

About RIMD

RIMD Awards

Best Presentation Award, The 9th Basic Biology Forum of Young Scientists,
GraduateSchool of Medicine, Osaka University

2017-18

Hiroyasu Kidoya Dept. of Signal Transduction2017.9.20

Award of Excellence for PhD. in Medicine, Kyushu University 2017
Masahiro Nagata Dept. of Molecular Immunology

2017 Tadamitsu Kishimoto International Travel Award
Mayuko Shimoda Dept. of Host Defense

2017.4.7

2017.4.11

International Session Award, The 57th Annual Meeting of the Japanese Respiratory Society
2017.5.9

2017.5.26

2017.6.10

2017.6.10

2017.6.15

ASV 2017 Postdoctoral Fellow Travel Award2017.6.24

2017.7.1

2017.7.11

2017.7.11

2017.7.13

2017.11.25

The 70th Annual Meeting of the Japanese Society for Bacteriology, in Kansai Region
2017.11.25

2017 JSI Human Immunology Research Award2017.12.13

2017 JSI Young Investigator Award2017.12.13

2017 JSI Young Investigator Award2017.12.13

Hisashi Kanemaru Dept. of Host Defense

2017.12.13

Best Presentation Award, The 46th Annual Meeting of The Japanese Society for Immunology

Japan Foundarion for Applied Enzymology

Hisashi Kanemaru Dept. of Host Defense
2017.8.9

Excellence Poster Award, KVSMO 2017 & 15th Japan-Korea Joint Symposium of Vascular Biology

64

Shihono Teruya Dept. of Molecular Bacteriology

2017 Ursula and Fritz Melchers Travel Award

The Best Award, Resarch Grant for Vascular Biology Innovation 2017,

Yumiko Hayashi Dept. of Signal Transduction

Incentive Award for Young Scientists,

Kohyuki Hirayasu Dept. of Host Defense

Masahito Ikawa Dept. of Experimental Genome Research Animal Resource Center

Hiroyasu Kidoya Dept. of Signal Transduction2017.11.21

Miwa Sasai Dept. of Immunoparasitology

Society for the Study of Reproduction, SSR Research Award 2017
for Infectious Diseases

2017.11.13

2017 Osaka University Prize

Taroh Kinoshita Yabumoto Department of Intractable Disease Research

Travel Award, KVSMO 2017 & 15th Japan-Korea Joint Symposium of Vascular Biology
Yumiko Hayashi Dept. of Signal Transduction2017 Takeda Prize

Sarunporn Tandhavanant Dept. of Bacterial Infections

Travel Award, KVSMO 2017 & 15th Japan-Korea Joint Symposium of Vascular Biology
Muramatsu Fumitaka Dept. of Signal Transduction2017.10.30

Incentive Award for Young Scientists,

Kirinjuku, Society for young scientists in hematology, The 13th Kirin-ji Prize
Takashi Satoh Dept. of Host Defense

2017.10.28

The 70th Annual Meeting of the Japanese Society for Bacteriology, in Kansai Region

Incentive Award for English Presentation, The Japanese Society of Child Neurology

Yutaka Terada Laboratory of Clinical Research on Infectious Diseases

Shojiro Haji Dept. of Molecular Immunology

Takashi Satoh Dept. of Host Defense

Incentive Award, The 9th Signal Network Workshop

Yoshiko Murakami Yabumoto Department of Intractable Disease Research

Research Incentive Award, Study Group for Clinical Research in Medicine

Taroh Kinoshita Yabumoto Department of Intractable Disease Research

Incentive Award, The 9th Signal Network Workshop

Teruhisa Tsukamoto Dept. of Oncogene Research2017.10.26

Miyuki Watanabe Dept. of Molecular Immunology

Yoshitaka Fujihara Dept. of Experimental Genome Research Animal Resource Center

Tetsuya Kimura Dept. of Oncogene Research

Ryotaro Nouda Dept. of Virology

Kishimoto Travel Awards by the International Cytokine and Interferon Society 2017

Japanese Association for Laboratory Animal Science 2017 Incentive Award
for Infectious Diseases

2017.10.25

Best Poster Award, The 65th Annual Meeting of the Japanese Society for Virology

by the Minister of Education, Culture, Sports, Science and Technology

Kiyoharu Fukushima Dept. of Host Defense

2017 Sugiura Incentive Award, the Japanese Society for Virology
Takasuke Fukuhara Dept. of Molecular Virology

The Young Scientists' Prize of The Commendation for Science and Technology

Takashi Satoh Dept. of Host Defense

2017.9.25

2017.8.25

2018.2.28

Highly cited researchers 2017
Shizuo Akira

Dept. of Host Defense

Shintaro Sato

Mucosal Vaccine Project

Masahiro Yamamoto

Dept. of Immunoparasitology
65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

66

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〜

67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.

Thailand

Maesot：Mae Sot General Hospital
Mae La refugee camp
Mae Tao Clinic
Maeramad Hospital
Shoklo Malaria Research Unit
Udonthani：

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.

68

Osaka University ICHO Festival

Summer Seminar for high school studets69

> 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/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/> Osaka University International Students Association
http://ouisa.info/

RIMD and IFReC conducts world-class researches in biological fields> Osaka University Brothers and Sisters Program (BSP)

collaborate each other to promote researches and foster talented humanincluding the fields of microbiology and immunology. RIMD and IFReCAn International-exchange circle organized by Osaka University
Students to support international students.

resources in these fields.

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

achievements in of RIMD and IFReC to the whole of society. In addition, theThe BIKEN foundation develops vaccines, thereby to translate the researchfoundation is dedicated to promote basic research by through the Taniguchi
Memorial Scholarship program and the BIKEN Center for Innovative Vaccine
Research Alliance Laboratories.

70

71

Grad Students Studying in RIMD

Why RIMD?

Research Interest

I always find medical world as an interesting world todive in. The treatment to human diseases which is still
undercover encourages me to search for the answers.
During my final year of undergraduate program inIndonesia, I put my focus on vaccine development and it
brought me to RIMD as one of research institutes in theworld that studies human diseases caused by
microorganisms. At that time, RIMD offers ascholarship, especially for Indonesian students, whowant to pursue graduate degree at Osaka University.
Since then, I am sure to continue my passion forresearch in RIMD.

I am feeling grateful that I belong to Molecular
Virology lab with Matsuura sensei as the supervisor.
The research interests in Matsuura lab are hepatitis
virus, flavivirus, and other RNA viruses. As for me, mycurrent research project is about hepatitis B virus (HBV).
Since the treatments of hepatitis B disease are
expensive and have a potential emergence todrug-resistant strains of HBV, finding a new drug for
HBV treatment is essential. Therefore, I am doing drug
screening that can suppress HBV infection, while alsofinding the responsible host factors for the infection.

Message for young students

A day in the life
I just finished Master program and am currently
continuing my journey to Ph.D.. Becoming Ph.D.
students in Japan is not so different with Masterstudents since the main goals of graduate students inJapan are to conduct researches and publish papers.
Besides doing experiments in lab, I love traveling anddoing photography. I also join Indonesian Student
Association in Osaka to keep in touch with otherIndonesian students. I am feeling comfortable with mylife in Osaka as I like the atmosphere, food, andkind-hearted Japanese people here. Finally, learning
Japanese language is so much challenging yet fun andinteresting!

I always think that having the status as a young student
is really precious. We have the spirit, energy, clear mind,
and much time to do anything that we want. But, doing
positive things will be much more worthy as we can givecontributions through our works to the society, even to
the world. Thus, I want to encourage young students tocome out of your comfort zones and pursue yourdreams, no matter how difficult they seem. Most
importantly, do not lose hope and keep going if you failbecause you will feel the best feeling of success once
you overcome the failure.

Yuzy Fauzyah
Department of Molecular Virology (Matsuura Lab)
Doctoral Course in Graduate School of Frontier Biosciences,
Osaka University

72

Why RIMD?
Since I entered the university, I had the chance toexperience research in Canada and France and I grewcurious about how research was done in Japan. As I was
also eager to learn more about this country’s culture andlanguage, it seemed like a great choice for a Ph.D..
During my master’s course, I developed an interest in theinterface between pathogens and immunity, particularly
the innate immune system and its receptors. I wasfortunate to be accepted into Professor Yamasaki’s
research team in which one of the aims is to study theC-type lectin receptor (CLR) family and investigate theirrole in immunity.

A day in the life
As a Ph.D. student, time is mainly focused on research
activities. Having a project as well as trying to solve andanswer biological questions is a challenging, but also a
fascinating undertaking. However, sharing, exchanges
and discussion, either with colleagues in the Lab and theinstitute or with researchers during conferences, is also
an enriching and essential part of our work. We also
have the possibility to get involved in teachingundergraduate and internship students, which is both
important and motivating.

Research Interest
Because we are vaccinated from a very young age, I
grew up with the impression that the adaptive immune
system was the spearhead of the host defense against
pathogens. Immunology classes showed me that the
innate immunity is in fact instrumental in theestablishment of an efficient response, as innate
immune cells are generally the first to sense pathogens
through their pattern recognition receptors, such as
TLRs or NLRs.
We are interested in the study of CLRs, that were shown
to recognize a wide range of pathogens (fungi,
mycobacteria…), but also endogenous molecules. We
are now trying to identify new ligands, and through astructural approach, describe the binding properties ofthese receptors.

Message for young students
Achieving a graduate school program in an entirely new
environment and country sounds like a tall order,
because it is. But the reward is even higher. It is theopportunity to push one's limits, to adapt, share withothers and to broaden your horizons in a uniquelocation. It goes without saying that I could not havegotten where I am now without the help of those aroundme, in and outside of the Lab. Therefore, I wish the samefor the newly arrived students and that they will be able
to succeed and make to most of their time in RIMD andOsaka University.

Zakaria Omahdi
Department of Molecular Immunology (Yamasaki Lab)
Doctoral Course in Graduate School of Medicine,
Osaka University.

73

RIMD STAFF

BUILDING AREA

●Staffs●Graduate Students①②

Professor

13

Graduate school of Medicine 51

11

Endowed Chair Professor

2

Graduate school of Science

6

12

Associate Professor

21

Graduate school of Pharmaceutical Science

3

1

Assistant Professor

22

Graduate school of Frontier Biosciences 13-

SA Professor

2

SA Associate Professor

9

SA Assistant Professor

8

SA Researcher

23

SA staff

13

Educational Support Staff

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

Technical Staff

3

Special research students

7Part-time Gneral & Technical Staff

43

Research students

6

Administrative Staff

21

JSPS Research fellows

1② South Building① Main Building (left)⑪ Cutting-edge Research
Building for Infectious
Diseases (right)

Total 183
(SA: Specially Appointed)⑦ Central Laboratory for
Biological Hazardous Microbes
and (back)⑤⑥ Animal Resource Center(left,front)

ACCOUNTS
Other Research Grants
117,341

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

Management Expenses Grant (Personnel)
914,552

3

7

Health and Labor Sciences Research Grants
2,100

12

13

6
9

MEXT Research Grants
408,050

8

5

4
10
1

Donations for Research
143,991
Cooperation Research
122,549

11

Total

3,148,069

2

unit: thousand yen

Collaborative Research
918,053

74

Management Expenses Grant(Non-Personnel)
521,432

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

75

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
Byoin Mae5

to find our mor

obiology,
immunolog y, micr
in
te
itu
st
in
ch
ar
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’ s ou tstanding re
is field by
RIMD is the world
development in th
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oncology and biol
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re so ur ce s de ve lo
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m
hu
t
or
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su
ch . W e wo rk to
on co ge ni c re se arld.
research in this fie
ntac t us topromote advanced
in RIMD. Please co
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ar
se
re
e
tiv
va
enable to fuel inno
r research.
Your suppor t will
w by suppor ting ou
ro
or
m
to
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how you can help
learn more about

How your donations

are utilized

erseas.
MD researches ov
arships etc.)
udy in RIMD (Schol
st
to
t
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ud
st
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in
● Helpin RIMD.
l students to study
na
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● Helpctious Diseases
se on Tropical Infe
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Co
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ni
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● Helpfor clinical doctors.
n-scientists
and seminars for no
es
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● Organizing● Suppor ting RI

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

Hotarugaike

Osaka (Itami)
AirportTOYONAKA
CampusTrain
12-minute walk from “Kita-Senri” Station
on Hankyu Senri Line.

Saito-nishi

SUITA
CampusHandai Byoin Mae

Shibahara Senri-Chuo Yamada

Ibaraki-Shi

IbarakiMinamiIbaraki

Shin-Osaka
Awaji
Juso

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 Hospital

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/
ak
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n.
ki
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https://wwthe Website
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Please make yocilities>d<Institutes an Fa
Diseases
te for Microbial■Research Institu
l Vaccine Fund
pment of Malaria
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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).
3

7677