173International Vaccine Design Center

Division of Infection Immunology(Human Immune-Profiling Team)

ヒト免疫プロファイリング系・感染免疫学分野
Professor
Cevayir COBAN, M.D., Ph.D. (Clinical Microbiology)
Visiting Professor
Anavaj SAKUNTABHAI, M.D., Ph.D.
Project Assistant Professor Michelle S.J. LEE, Ph.D.

教 授 博士（医学）（臨床微生物学位） チョバン ジェヴァイア
客員教授 博士（医学）サクンタバイ アナヴァジ
特任助教 博士（医学）リー ミシェル

As a member of the International Vaccine Design Center of IMSUT, we focus on
elucidating host-pathogen interactions in the context of emerging infectious
diseases such as dengue and Covid19 and the neglected tropical diseases (i.e.
malaria, leishmaniasis), to understand the virulence factors of these pathogens andultimately to design successful vaccines against them.

1.  Adjuvant discovery and development platform
Adjuvants are considered essential vaccine components for enhancing vaccine responses. As a member of IMSUT International Vaccine Design Center(https://vdesc.ims.u-tokyo.ac.jp/en/), we have systematically screened innate and adaptive immune signaling molecules involved in the mode of action (MOA)of adjuvants and vaccines. Recently, we have been
involved in the discovery of novel adjuvants as part of
the AMED SCARDA project. Our recent projects havefocused on investigating B cell development and thepathways involved in germinal center (GC) formation
for the generation of potent antibody responses
against infections and during vaccination. We foundthat TBK1, the well-known innate immune signaling
kinase that controls antiviral immune responses andnucleic acid-mediated type I interferon responses, isvery important for the generation of GCs that confer
sterile immunity to reinfection (Lee et al., J Exp Medicine, 2022).
2.  Elucidation of host-pathogen interactions

Our laboratory has investigated several aspects ofimmunopathology caused by Plasmodium parasites.
We have recently studied the immunopathology ofcerebral malaria, the deadliest complication of humanmalaria infection, in the brain using the CUBIC clearance technique (Matsuo-Dapaah et al., Int Immunology,2021). The 3D reconstruction of malaria-infected brain
showed that olfactory bulb is disrupted during experimental cerebral malaria. We have recently made significant progress in understanding new cell types that
accumulate/reside in the olfactory bulb and interactwith Plasmodium parasites. Chronic bone loss is anunforeseen complication of malaria which is mediated via MyD88 adaptor protein (Lee et al,. Science Immunology, 2017). We have been studying to address
the crucial cell types important for MyD88-mediatedbone loss. We also investigate bone marrow niches responsible for malaria-induced loss of memory.
3.  Infection and cancer
Previously, we investigated the role of Lipocalin 2(LCN2, also known as siderocalin or neutrophil ge-174
latinase-associated lipocalin (NGAL)) in malaria infection that bolsters innate and adaptive immune responses to malaria infection through modulation ofiron metabolism (Zhao et al., Cell Host Microbe, 2012).
LCN2 expression is also increased in cancer. In carcinogenesis stroma-associated immunity is an important regulator of tumor growth. Tumor cells create a
microenvironment by releasing various mediators tomaintain their presence and spread. Due to the infiltration of monocytes and leukocytes in tumor microenvironment, it is hypothesized that the iron balance is disrupted by excessive iron consumption,
possibly leading to increased expression of LCN2 as
an intracellular iron transporter. We recently investigated the expressions of programmed cell death ligand-1 (PD-L1) and LCN2 in breast cancers with various molecular subtypes, along with their correlations
with other prognostic indicators, including Ki-67,
lymph node metastasis, histological grade, tumor-infiltrating lymphocyte (TILs) accumulation, and necrosis. We found that there is an association of LCN2
with known prognostic factors and molecular subtypes. Moreover, significant elevations of LCN2 andPD-L1 expressions were observed in triple-negativeand HER2-positive breast cancers. The findings fromthis research may contribute to the immunotherapeutic application of LCN2 and its prognostic significancein breast cancer management (Ekemen et al., Breast
Cancer: Targets and Therapy, in press).

4.  Infection and host genetics
The genetics of an individual contributes to thesusceptibility and response to viral infections. International groups including Prof. Sakuntabhai’s groupformed a global network of researchers to investigate
the role of human genetics in SARS-CoV-2 infection
and COVID-19 severity (COVID-19 Host Genetics Initiative. Mapping the human genetic architecture of COVID-19. Nature 600, 472–477, 2021). Investigating therole of host genetic factors in COVID-19 severity andsusceptibility can inform our understanding of theunderlying biological mechanisms that influence adverse outcomes and drug development. Recently,
they published a second update on mapping the human genetic architecture of COVID-19 (The COVID-19
Host Genetics Initiative. A second update on mapping thehuman genetic architecture of COVID-19. Nature 621,E7–E26, 2023). They performed a meta-analysis of up
to 219,692 cases and over 3 million controls. They expanded the current knowledge of host genetics for
COVID-19 susceptibility and severity by further doubling the case numbers from the previous data releaseand identifying 28 additional loci. Notably, they observed severity loci mapped to type I interferon pathway, while susceptibility loci mapped to viral entry
and airway defense pathways, with notable exceptions for severity-classified TMPRSS2 and MUC5Bloci.

Publications
Ekemen S, Bilir E, Soultan HEA, Zafar S, Demir F,
Tabandeh B, Toprak S, Yapicier O, Coban C. The
Programmed Cell Death Ligand 1 and Lipocalin 2
Expressions in Primary Breast Cancer and Their
Associations with Molecular Subtypes and Prognostic Factors. Breast Cancer: Targets and Therapy,2023, in press.
Becker HJ, Ishida R, Wilkinson AC, Kimura T, Lee
MSJ, Coban C, Ota Y, Tanaka Y, Roskamp M, SanoT, Tojo A, Kent DG, Yamazaki S. Controlling genetic heterogeneity in gene-edited hematopoietic stem
cells by single-cell expansion. Cell Stem Cell, Jul
6;30(7):987-1000.e8. doi: 10.1016/j.stem.2023.06.002,2023.
Ekemen S, Comunoglu C, Kayhan CK, Bilir E, Cavusoglu I, Etiler N, Bilgi S, Ince U, Coban C, Erden HF.
Endometrial Staining of CD56 (Uterine NaturalKiller), BCL-6, and CD138 (Plasma Cells) Improve
Diagnosis and Clinical Pregnancy Outcomes in Unexplained Infertility and Recurrent IVF Failures:Standardization of Diagnosis with Digital Pathology. Diagnostics, 13(9):1557. doi.org/10.3390/diagnostics13091557, 2023.
Dott T, Culina S, Chemali R, Mansour CA, Dubois F,Jagla B, Doisne JM, Rogge L, Huetz F, Jönsson F,Commere PH, Di Santo J, Terrier B, Quintana-Mur-ci L, Duffy D, Hasan M; Milieu Intérieur Consortium. Standardized high-dimensional spectral cytometry protocol and panels for whole blood
immune phenotyping in clinical and translational
studies. Cytometry A. Sep 26. doi: 10.1002/cyto.a.
24801, 2023.
Tawfik A, Kawaguchi T, Takahashi M, Setoh K, Yamaguchi I, Tabara Y, Van Steen K, Sakuntabhai A, Matsuda F. Trivalent inactivated influenza vaccine response and immunogenicity assessment after oneweek and three months in repeatedly vaccinatedadults. Expert Rev Vaccines. Jan-Dec;22(1):826-838.
doi: 10.1080/14760584.2023.2262563. Epub 2023 Oct
6, 2023.
COVID-19 Host Genetics Initiative. A second updateon mapping the human genetic architecture of
COVID-19. Nature. 2023 Sep;621(7977):E7-E26. doi:
10.1038/s41586-023-06355-3. Epub 2023 Sep 6.
PMID: 37674002
Villain E, Chanson A, Mainka M, Kampschulte N, Le
Faouder P, Bertrand-Michel J, Brandolini-Bulon M,Charbit B, Musvosvi M, Bilek N, Scriba TJ, Quintana-Murci L, Schebb NH, Duffy D, Gladine C; Milieu Interieur Consortium. Integrated analysis ofwhole blood oxylipin and cytokine responses after
bacterial, viral, and T cell stimulation reveals new175
immune networks. iScience. 2023 Jul 18;26(8):107422.
doi: 10.1016/j.isci.2023.107422. eCollection 2023

Aug 18. PMID: 37575177