Lee, Seung-Hwan - University of Ottawa - Department of Biochemistry, Microbiology and Immunology

个人简介

B.Sc. ChonBuk National University, South Korea M.Sc. ChonBuk National University, South Korea Ph.D. University of Ottawa Post-doc. Brown University, USA

研究领域

My primary research goal is to understand host-pathogen interactions during clinically important virus infection, and to direct this knowledge toward therapeutic approaches with favorable consequences. Host immunity to pathogens is multifaceted, involving cell-to-cell interactions and communication among many different cells via cytokines. Dissection of such a complex network of immune responses requires extensive knowledge of the infection system and careful examination at optimal conditions. Cytomegalovirus (CMV) is an opportunistic pathogen which can cause serious diseases in immunocompromised individuals such as HIV-infected patients and organ recipients. My previous and current research have focused on understanding the immune response mediated by the Natural Killer (NK) activating receptor Ly49H during murine cytomegalovirus (MCMV) infection, leading to several seminal contributions, in which I demonstrated the identification of the Ly49h gene as a resistant gene, the generation of Ly49H-transgenic mice, the generation of Ly49H-deficient mice, and the identification of a novel pathway mediated by Ly49H during prolonged infection to regulate CD8 T cell responses. This work has served to establish one of the most powerful models for the study of the roles of an NK activating receptor in viral infections. Given my continued interest in NK regulation during virus infection, here I propose the following aims for my future research program. Aim 1: Identification of the Pathways Resulting in NK Cell Loss during Persistent Infection My previous work showed that in the absence of the Ly49H activating receptor, NK cell populations are depleted in response to persistent infection. Based on the hypothesis that NK cell loss results from activation of a cell death pathway, presumably apoptosis, and that the activation signal through Ly49H dominantly rescues NK cells from such cell death signal, we plan to examine potential mediators of NK cell death in Ly49h-/- mice. Specifically, we will focus on Type 1 interferon (IFN), which has been shown to mediate a number of functions in NK cells. Given that IFNα/β-mediated apoptosis has been reported in other cell types, it is conceivable that the high systemic levels of IFNα/β resulting from uncontrolled virus replication during MCMV infection in the absence of Ly49H could lead to apoptosis in NK cells. Aim 2: Investigation of NK cell Immunoregulatory Functions A critical question raised by my previous findings on the production of IL-10 by NK cells concerns the mechanism by which cytokine expression is induced in this cell population. Stimulation through either activating or cytokine receptors are two major stimulatory pathways for NK cell cytokine production. Once conditions endowing NK cell regulatory functions are characterized, this knowledge, in combination with the established protocol for NK cell expansion ex vivo, will be applied for the evaluation of the NK cell regulatory role in virus infections in which T cell-mediated immunopathology is prominent. With these aims, I plan to extend my current research to discover a novel mechanism for NK regulation. The immunological significance of such regulation is a topic of great interest. In particular, most emerging pathogens elicit strong acute immune responses resulting in severe NK losses. Progress of the proposed research will undoubtedly open new avenues for therapeutic regulation in a variety of infection including those of emerging pathogens.

近期论文

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Ahmad Bakur Mahmoud, Megan M. Tu, Haggag S. Zein, Mir Munir A. Rahim, Andrew Wight, Seung-Hwan Lee, Harman S. Sekhon, Earl G. Brown, Andrew P. Makrigiannis. Influenza virus targets class I MHC-educated NK cells for immunoevasion. Accepted to Plos Pathogen. Alaa Kassim Ali, Jun Seok Oh, Eric Vivier, Meinrad Busslinger and Seung-Hwan Lee. Natural killer cell-specific Gata3 ablation identifies the maturation program required for bone marrow exit and control of proliferation. J Immunol. 2016 Jan 15. pii: 1501593. [Epub ahead of print] Jun Seok Oh, Alaa Kassim Ali, Sungjin Kim, Daniel J. Corsi, Curtis Cooper and Seung-Hwan Lee. NK cells lacking FcεRIγ is associated with protection from liver damage in chronic HCV infection. Eur J Immunol. 2015 Dec 29. doi: 10.1002/eji.201546009. [Epub ahead of print] Alaa Kassim Ali, Neethi Nandagopal, and Seung-Hwan Lee. IL-15-PI3K-AKT-mTOR: The pathway taking care of life journey of Natural Killer cells. Frontiers in Immunology 6:355. doi: 10.3389/fimmu.2015.00355. 2015. HeeJo Baek, Da-Woon Kim, Minh-Trang Thi Phan, Ju-Sun Kim, Jihoon Yang, Jeong-il Choi, JeJung Lee, Myung-Geung Shin, Dong-Wook Ryang, Sang-Ki Kim, Seung-Hwan Lee, Hoon Kook, Duck Cho. Comparison of FcR-deficient natural killer cells between cord and adult blood in the cytomegalovirus-endemic Korean population. Annals of Laboratory Medicine, 35, 423-8, 2015. Neethi Nandagopal, Alaa Ali, Amandeep Komal and Seung-Hwan Lee. The Critical Role of IL-15-PI3K-mTOR Pathway in Natural Killer Cell Effector Functions. Frontiers in Immunology 5:187. doi: 10.3389/fimmu.2014.00187. 2014. Margarite L. Tarrio*, Seung-Hwan Lee*, Maria F. Fragoso, Hong-Wei Sun, Yuka Kanno, John J. O’Shea, and Christine A. Biron. Proliferation Conditions Promote Intrinsic Changes in NK Cells for an IL-10 Response. Journal of Immunology 193, 354-363, 2014. *Equal contribution. Dong-Pyo Lim, Youn-Young Jang, Seokho Kim, Sang Seok Koh, Je-Jung Lee, Ju-Sun Kim, Minh-Trang Thi Phan, Dong-Jun Shin, Myung-Geun Shin, Seung-Hwan Lee, Meesun Yoon, Sang-Ki Kim, Jung-Han Yoon, Min-Ho Park, Duck Cho. Effect of exposure to IL-21 at various time points on the ex vivo expansion of human natural killer cells. Cytotherapy 14, S1465-3249, 2014. Seung-Hwan Lee*, Maria F. Fragoso*, and Christine A. Biron. Cutting Edge: A Novel Mechanism Bridging Innate and Adaptive Immunity: IL-12 Induction of CD25 To Form High-Affinity IL-2 Receptors on NK Cells. Journal of Immunology 189, 2712-2716, 2012. *Equal contribution. M. Pilar Gil, Mickaël J. Y. Ploquin, Wendy T. Watford, Seung-Hwan Lee, Kwangsin Kim, Xin Wang, Yuka Kanno, John J. O’Shea, and Christine A. Biron. Regulating type 1 IFN effects in CD8 T cells during viral infections: changing STAT4 and STAT1 expression for function. Blood, 120, 3718-3728, 2012. Seung-Hwan Lee, and Christine A. Biron. Here Today – Not Gone Tomorrow: Roles for Activating Receptors in Sustaining NK Cells for Function During Viral Infections. European Journal of Immunology 40, 923-932, 2010. Seung-Hwan Lee, Kwang-Sin Kim, Nassima Fodil-Cornu, Silvia M. Vidal, and Christine A. Biron. Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infection. The Journal of Experimental Medicine 206, 2235-2251, 2009 (Highlighted in Nature Immunology Reviews). Nassima Fodil-Cornu, Seung-Hwan Lee, Simon Belanger, Andrew P. Makrigiannis, Christine A. Biron, R. Mark Buller and Silvia M. Vidal. Ly49h deficient C57BL/6 mice: a new MCMV susceptible model remains resistant to unrelated pathogens controlled by the Natural Killer gene Complex. Journal of Immunology 181, 6394-6405, 2008. Seung-Hwan Lee, Takuya Miyagi, and Christine A. Biron. Keeping NK cells in highly regulated antiviral warfare. Trends in Immunology, 28, 252-259, 2007 (Featured in Issue cover). Seung-Hwan Lee, Ken Dimock, Douglas A Gray, Nicole Beauchemin, Kathryn V. Holmes, Majid Belouchi, John Realson, Silvia M. Vidal. Maneuvering for advantage: the genetics of mouse susceptibility to virus infection. Trends in Genetics. 8, 447-457, 2003. Zoha Kibar, Susan Gauthier, Seung-Hwan Lee, Silvia Vidal and Philippe Gros. Rescue of the neural tube defect of loop-tail mice by a BAC clone containing the Ltap gene. Genomics 82, 397-400, 2003. Seung-Hwan Lee, Ahmed Zafer, Yves de Repentigny, Rashmi Kothary, Michel L. Tremblay, Philippe Gros, Pascale Duplay, John R. Webb and Silvia M. Vidal. Transgenic expression of the activating natural killer receptor Ly49H confers resistance to cytomegalovirus infection in genetically susceptible mice. The Journal of Experimental Medicine 197, 515-526, 2003. Eduardo Diez, Seung-Hwan Lee, Susan Gauthier, Silvia M. Vidal and Philippe Gros. Birc1e (Naip5) is the Legionella pneumophila resistance locus Lgn1. Nature Genetics 33, 55-60, 2003. Seung-Hwan Lee, John R. Webb, Silvia M. Vidal. Innate immunity to cytomegalovirus: the Cmv1 locus and its role in natural killer cell function. Microbes and infection 4, 1491-1503, 2002. Seung-Hwan Lee, Silvia M. Vidal. Functional diversity of Mx proteins: variations on a theme of host resistance to infection. Genome Research 12, 527-530, 2002. John R. Webb, Seung-Hwan Lee and Silvia M. Vidal. Genetic control of innate immune responses against cytomegalovirus: MCMV meets its match. Genes and Immunity 3, 250-262, 2002. Seung-Hwan Lee, Sonia Girard, Denis Macina, Maria Busa, Ahmed Zafer, Abdelmajid Belouchi, Philippe Gros and Silvia M. Vidal. Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily. Nature Genetics 28, 42-45, 2001 (Highlighted in News and Views).