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Investigating the Role of Innate Inflammatory Pathways During Infection with Murine Coronavirus University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2015 Investigating the Role of Innate Inflammatory Pathways During Infection With Murine Coronavirus Zachary Bestor Zalinger University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Allergy and Immunology Commons, Immunology and Infectious Disease Commons, Medical Immunology Commons, and the Virology Commons Recommended Citation Zalinger, Zachary Bestor, "Investigating the Role of Innate Inflammatory Pathways During Infection With Murine Coronavirus" (2015). Publicly Accessible Penn Dissertations. 2123. https://repository.upenn.edu/edissertations/2123 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2123 For more information, please contact [email protected]. Investigating the Role of Innate Inflammatory Pathways During Infection With Murine Coronavirus Abstract Multicellular organisms are constantly exposed to microorganisms, such as viruses and bacteria, many of which are infectious pathogens. The immune system evolved to provide protection against these organisms, and includes numerous components to defend against a diverse, rapidly evolving pool of pathogens. The immune system is classically divided into two arms, the innate and adaptive systems. The time and metabolic cost of activating the T and B cell responses are considerable, and can also have deleterious side effects if the response is not properly controlled. Therefore, the adaptive immune system is carefully regulated so as to be activated only when necessary. The innate immune system serves to control most pathogens in a more rapid, less energetically expensive manner than the adaptive immune system, and to help regulate subsequent immune responses, guiding and controlling them in order to most efficiently clear pathogens with a minimum of pathological side effects. Among the first elements of the innate system that pathogens encounter are pattern recognition receptors, invariant receptors that detect conserved pathogen associated molecular patterns. Upon recognizing its binding ligand, a pattern recognition receptor will activate a signaling cascade that often triggers production and/or release of one or more pro- inflammatory cytokines. These in turn modulate additional elements of both the innate and adaptive immune responses, and are often critical lynchpins of host defense. Due to this central role in the immune system we investigated the roles of two distinct innate inflammatory pathways, the inflammasome and the MDA5-dependent portion of the type 1 interferon response, during infection with the murine coronavirus mouse hepatitis virus (MHV). Utilizing transgenic mice deficient in Caspase-1 and -11, which catalyze all inflammasome processing, the IL-1 receptor, the IL-18 receptor, or MDA5, we characterize the disease course and subsequent immune response following infection with MHV, a model murine coronavirus. We find that inflammasome signaling is otectivpr e during infection, and that much or all of this protection is mediated by IL-18 signaling driving production of interferon gamma by T cells. We also demonstrate that MDA5 signaling controls viral tropism and replication, and that in its absence the host immune response becomes over active, likely leading to lethal pathology. Overall, our studies help define how innate inflammatory pathways can have diverse influences on pathogenesis and the immune response. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Susan R. Weiss Subject Categories Allergy and Immunology | Immunology and Infectious Disease | Medical Immunology | Virology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2123 INVESTIGATING THE ROLE OF INNATE INFLAMMATORY PATHWAYS DURING INFECTION WITH MURINE CORONAVIRUS Zachary B. Zalinger A DISSERTATION in Cell and Molecular Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2015 Supervisor of Dissertation _____________________ Susan R. Weiss Professor of Microbiology Graduate Group Chairperson _____________________ Daniel S. Kessler, Associate Professor of Cell and Developmental Biology Dissertation Committee: Igor E. Brodsky, Assistant Professor of Pathobiology Christopher A. Hunter, Professor of Pathobiology Dennis L. Kolson, Professor of Neurology Glenn F. Rall, Professor, Fox Chase Cancer Center Luis J. Sigal, Professor, Jefferson University INVESTIGATING THE ROLE OF INNATE INFLAMMATORY PATHWAYS DURING INFECTION WITH MURINE CORONAVIRUS COPYRIGHT 2015 Zachary B. Zalinger This work is licensed under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 License To view a copy of this license, visit http://creativecommons.org/licenses/by-ny-sa/2.0 ACKNOWLEDGMENTS I would like to thank my mentor, Dr. Susan Weiss, for her support and guidance, and the members of her laboratory for their patience. I would also like to thank my friends and classmates in Philadelphia, who have made these long years tolerable, and the completion of my time here bittersweet. I will miss them all. I am especially thankful for Dr. Cierra Casson, whose brilliance and love has made all the difference. Without her I would not be standing here today. And finally I would like to thank my family for all their support and acceptance over the years. My parents, Wendy Bestor and Lee Zalinger, who taught me that knowledge has its own value. And my grandfathers, Dr. Alvin Zalinger, who I never knew but who I hope would have been proud of me, and Dr. Charles Bestor, who has always been a shining example of the value of the intellectual life. iii ABSTRACT INVESTIGATING THE ROLE OF INNATE INFLAMMATORY PATHWAYS DURING INFECTION WITH MURINE CORONAVIRUS Zachary B. Zalinger Susan R. Weiss Multicellular organisms are constantly exposed to microorganisms, such as viruses and bacteria, many of which are infectious pathogens. The immune system evolved to provide protection against these organisms, and includes numerous components to defend against a diverse, rapidly evolving pool of pathogens. The immune system is classically divided into two arms, the innate and adaptive systems. The time and metabolic cost of activating the T and B cell responses are considerable, and can also have deleterious side effects if the response is not properly controlled. Therefore, the adaptive immune system is carefully regulated so as to be activated only when necessary. The innate immune system serves to control most pathogens in a more rapid, less energetically expensive manner than the adaptive immune system, and to help regulate subsequent immune responses, guiding and controlling them in order to most efficiently clear pathogens with a minimum of pathological side effects. Among the first elements of the innate system that pathogens encounter are pattern recognition receptors, invariant receptors that detect conserved pathogen associated molecular patterns. Upon recognizing its binding ligand, a pattern recognition receptor will activate a signaling cascade that often triggers production and/or release of one or more pro- inflammatory cytokines. These in turn modulate additional elements of both the innate and adaptive immune responses, and are often critical lynchpins of host defense. Due to this central role in the immune system we investigated the roles of two distinct innate inflammatory pathways, the inflammasome and the MDA5-dependent portion of the type 1 interferon response, during infection with the murine coronavirus mouse hepatitis virus (MHV). Utilizing transgenic mice deficient in Caspase-1 and -11, which catalyze all inflammasome processing, the IL-1 receptor, the IL-18 receptor, or MDA5, we characterize the disease course and subsequent immune response following infection with MHV, a model murine coronavirus. We find that inflammasome signaling is protective during infection, and that much or all of this protection is mediated by IL-18 signaling driving production of interferon gamma by T cells. We also demonstrate that MDA5 signaling controls viral tropism and replication, and that in its absence the host immune response becomes over active, likely leading to lethal pathology. Overall, our studies help define how innate inflammatory pathways can have diverse influences on pathogenesis and the immune response. iv TABLE OF CONTENTS Content Page ACKNOWLEDGMENT…………………..…………………………………………..………….iii ABSTRACT……..…………………………………………………………………………..……iv TABLE OF CONTENTS…………………………………………………………...…………….v LIST OF ABBREVIATIONS…………………………………………………….……………...vii LIST OF ILLUSTRATIONS…..………………………………………………………………..viii CHAPTER 1: INTRODUCTION…….………………………………………..…………………1 A. Structure and function of the inflammasome……………………………….………..3 B. Ligands of inflammasome sensors………………………………………….………...4 C. The non-canonical inflammasome……………………………………….……………6 D. Inflammasome-mediated cell death………………………………….………………..7 E. IL-1 signaling…………………………………………………………………………….8 F. IL-18 signaling…………………………………………………………………………...9 G. Role of the inflammasome in demyelination……………………….……………….10 H. Structure and function of MDA5…………………………………….………………..12 I. MDA5’s binding substrate(s) …………………………………….…………………..14 J. The type 1 interferon signaling pathway…………………………………………….14 K. The role of type 1 interferon during acute infection………………………………..15 L. The interferon
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