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Hantaviruses Vs Programmed Cell Death

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Hantaviruses Vs Programmed Cell Death From THE DEPARTMENT OF MICROBIOLOGY, TUMOR AND CELL BIOLOGY Karolinska Institutet, Stockholm, Sweden WHO IS KILLING WHOM? HANTAVIRUSES VS PROGRAMMED CELL DEATH Shawon Gupta Stockholm 2016 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by E-Print AB 2016 © Shawon Gupta, 2016 ISBN 978-91-7676-150-2 Who is Killing Whom? Hantaviruses VS Programmed Cell Death THESIS FOR DOCTORAL DEGREE (Ph.D.) By Shawon Gupta Principal Supervisor: Opponent: Associate Professor Jonas Klingström Assistant Professor Jason Botten Karolinska Institutet The University of Vermont Department of Medicine, Huddinge Department of Medicine Center for Infectious Medicine Division of Immunobiology Examination Board: Co-supervisors: Professor Stefan Schwartz Professor Hans-Gustaf Ljunggren Lund University Karolinska Institutet Department of Laboratory Medicine Department of Medicine, Huddinge Division of Medical Microbiology Center for Infectious Medicine Associate Professor Vladimir Gogvadze Adjunct Professor Ali Mirazimi Karolinska Institutet Karolinska Institutet Institute of Environmental Medicine Department of Laboratory Medicine Unit of Toxicology Division of Clinical Microbiology Associate Professor Marianne Jansson Associate Professor Kerstin Falk Lund University Karolinska Institutet Department of Laboratory Medicine Department of Microbiology, Tumor Division of Medical Microbiology and Cell Biology To my family Deep into that darkness peering, long I stood there wondering, fearing… From The Raven by Edgar Allan Poe 1845 ABSTRACT Hantaviruses belong to the Bunyaviridae family of negative stranded RNA viruses. They carry a tri-segmented genome and consist of four structural proteins. The four structural proteins are two glycoproteins Gn and Gc, a nucleocapsid (N) protein and an RNA-dependent RNA-polymerase. An additional nonstructural protein can be expressed by some hantaviruses. Hantavirus-infection cause two severe diseases in humans with potential deadly outcome, namely hemorrhagic fever with renal syndrome (HFRS) or hantavirus cardio- pulmonary syndrome (HCPS). One main target for hantavirus-infection is the endothelial cells and vascular leakage is a hallmark for both HFRS and HCPS. In patients strong cytotoxic lymphocyte responses are seen. Cytotoxic lymphocytes, such as natural killer (NK) cells and cytotoxic T lymphocytes, cause apoptosis in virus-infected cells via the cytotoxic granule pathway or the death receptor pathway. The cytotoxic granule pathway uses granzyme B to facilitate programmed cell death (PCD) in the target. The death receptor pathway uses death ligands, among them tumor necrosis factor related apoptosis-inducing ligand (TRAIL) binds to death receptor (DR) 4 or 5, to induce PCD. One potential mechanism regarding hantavirus pathogenesis might be killing of infected endothelial cells by cytotoxic lymphocytes, thus causing leakage of the endothelium. This is contradicted by findings showing that in patient autopsy, hantavirus-infected cells are intact. The aim of this PhD thesis is to give a possible explanation of this dichotomy and to better understand hantavirus pathogenesis. The first part of this thesis (paper I and II) shows that hantavirus-infection protects cells from cytotoxic lymphocytes via inhibiting granzyme B activity and by down-regulating DR5 from the cell surface. Granzyme B and caspase 3, enzymes needed for apoptosis (a type of PCD), both interacts with hantavirus N protein, and they are both inhibited by the N protein. Further, hantavirus-infection of primary endothelial cells causes miss-localization of DR5. In infected cells DR5 is found in the nucleus instead of on the cell surface. Taken together, hantavirus-infection blocks the two major pathways used by cytotoxic lymphocytes to induce cell death, suggesting that hantavirus pathogenesis is not due to killing of infected cells by cytotoxic lymphocytes. The last part of this thesis (paper III) focuses on hantavirus activated NK cell mediated killing of uninfected endothelial cells. NK cells co-incubated with hantavirus-infected endothelial cells are activated. This activation is contact dependent and was attributed to IL-15 and IL-15Rα expression on hantavirus-infected cells’ surface. Interestingly, these activated NK cells induce cell death in uninfected cells with normal HLA class I levels, indicating that hantavirus might cause NK cell mediated killing of uninfected bystander cells. Taken together, the papers I, II and III included in this thesis shows that hantavirus- infection protects cells from cytotoxic lymphocyte mediated killing, while infected cells can cause NK cell activation and possibly subsequent NK cell killing of uninfected cells. LIST OF SCIENTIFIC PAPERS I. Gupta S, Braun M, Tischler ND, Stoltz M, Sundström KB, Björkström NK, Ljunggren HG, Klingström J. Hantavirus-infection Confers Resistance to Lymphocyte-Mediated Apoptosis. PLoS Pathogens, 2013 9(3):e1003272. II. Gupta S, Solà Riera C, Braun M, Björkström NK, Ljunggren HG, Klingström J. Hantavirus Causes Nuclear Translocation of Death Receptor 5 and Protects Infected Cells from TRAIL-Induced Apoptosis. Manuscript. III. Braun M, Björkström NK, Gupta S, Sundström K, Ahlm C, Klingström J, Ljunggren HG. NK Cell Activation in Human Hantavirus Infection Explained by Virus-Induced IL-15/IL-15Rα Expression. PLoS Pathogens, 2014 20;10(11):e1004521. CONTENTS INTRODUCTION ................................................................................................................ 1 ABOUT HANTAVIRUSES ......................................................................................... 1 The history ....................................................................................................................... 1 Hosts and distribution ...................................................................................................... 2 Diseases ........................................................................................................................... 3 Structure ........................................................................................................................... 3 Hantavirus proteins.......................................................................................................... 4 Life cycle ......................................................................................................................... 6 IMMUNOLOGY AND HANTAVIRUSES ............................................................... 7 Pattern recognition receptors .......................................................................................... 7 Nuclear factor kappa-light-chain-enhancer of activated B cells .................................... 8 Interferons ........................................................................................................................ 8 Dendritic cells .................................................................................................................. 9 Natural killer cells ......................................................................................................... 10 Cytotoxic T Lymphocytes ............................................................................................. 11 PROGRAMMED CELL DEATH ............................................................................ 12 Apoptosis ....................................................................................................................... 12 Intrinsic apoptosis .......................................................................................................... 13 Extrinsic apoptosis ........................................................................................................ 13 Caspases ......................................................................................................................... 13 Viruses and apoptosis .................................................................................................... 14 Granzyme B mediated cell death .................................................................................. 15 TRAIL-induced cell death ............................................................................................ 16 HANTAVIRUS PATHOGENESIS .......................................................................... 19 AIM....................................................................................................................................... 21 RESULTS AND DISCUSSION ........................................................................................ 23 Inhibition of chemically-induced apoptosis ................................................................. 23 Inhibition of cytotoxic granule-mediated apoptosis ..................................................... 24 Inhibition of a death ligand/receptor pathway .............................................................. 26 Aberrant localization of death receptor 5 ..................................................................... 27 NK cells activated by hantaviruses ............................................................................... 27 Activation through interleukin-15................................................................................. 29 An unexpected function of hantavirus activated NK cells ........................................... 29 CONCLUSIONS ................................................................................................................
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