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Department of Microbiology and Immunology

Division of Malaria Immunology
マラリア免疫学分野

Professor
Cevayir COBAN, M.D., Ph.D. (Clinical Microbiology)
Project Assistant Professor Michelle S.J. LEE, Ph.D.
Project Assistant Professor Jalal ALSHAWEESH, 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
特任助教 博士（医学）リー ミシェル
特任助教 博士（医学）アルシャウィシュ ジャラル

Summary of Activity (Less than 70 words)
Our laboratory focuses on the elucidation of host-pathogen interactions. We mainly
work on malaria, but also cover several infectious diseases such as leishmaniasis
and respiratory infections. We study both innate and adaptive immune responses
against these diverse pathogens in order to develop successful vaccines againstthem.

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. One of the recent findings is to understand how the combination of TLR9and STING agonists synergistically induce innate andadaptive responses to generate robust anti-tumor responses (Temizoz et al., International Immunology, 2022).
Our recent projects have focused on investigating B
cell development and the pathways involved in germinal center (GC) formation for the generation of potent antibody responses against infections and during
vaccination. We found that TBK1, the well-known innate immune signaling kinase that controls antiviral
immune responses and nucleic acid-mediated type I
interferon responses, is very 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 of
cerebral 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 interact
with 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 gelatinase-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, in addition to the accumulation of so-28
matic mutations, stroma-associated immunity is an
important regulator of tumor growth. Tumor cells
create a microenvironment by releasing various mediators to maintain their presence and spread. Due tothe infiltration of monocytes and leukocytes against
the tumor, it is hypothesized that the iron balance isdisrupted by excessive iron consumption, possibly
leading to increased expression of LCN2 as an intracellular iron transporter. We recently investigated theexpressions of programmed cell death ligand-1 (PDL1) and LCN2 in breast cancers with various molecular subtypes, along with their correlations with otherprognostic indicators, including Ki-67, lymph nodemetastasis, histological grade, tumor-infiltrating lymphocyte (TILs) accumulation, and necrosis. We foundthat there is an association of LCN2 with known
prognostic factors and molecular subtypes. Moreover, significant elevations of LCN2 and PD-L1 expressions were observed in triple-negative and HER2-positive breast cancers. The findings from this research
may contribute to the immunotherapeutic applicationof LCN2 and its prognostic significance in breast cancer management (Ekemen et al., Breast Cancer: Targetsand Therapy, in press).

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 TheirAssociations 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.