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Manipulation of Host Cell Death and Innate Immune Signaling Pathways by Coxsackievirus B3

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Manipulation of Host Cell Death and Innate Immune Signaling Pathways by Coxsackievirus B3 Manipulation of host cell death and innate immune signaling pathways by Coxsackievirus B3 by Katharine Grace Harris B.S. in Microbiology, Purdue University, 2010 Submitted to the Graduate Faculty of the School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Molecular Virology and Microbiology University of Pittsburgh 2015 UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This dissertation was presented by Katharine Grace Harris It was defended on May 4, 2015 and approved by Carolyn B. Coyne, PhD, Associate Professor of Microbiology and Molecular Genetics Jennifer Bomberger, PhD, Assistant Professor of Microbiology and Molecular Genetic Sarah Gaffen, PhD, Professor of Medicine Saumendra Sarkar, PhD, Assistant Professor of Microbiology and Molecular Genetics Jian Yu, PhD, Associate Professor of Pathology Dissertation Advisor: Carolyn B. Coyne, PhD, Associate Professor of Microbiology and Molecular Genetics ii Manipulation of host cell death and innate immune signaling pathways by Coxsackievirus B3 Katharine G Harris University of Pittsburgh, 2015 Coxsackievirus B3 (CVB), an enterovirus, is a small, ssRNA virus with a genome of approximately 7 kB. There are 2 million symptomatic CVB infections annually in the United States, ranging from mild febrile illnesses to myocarditis, meningoencephalitis, or pancreatitis. CVB is a fecal-oral pathogen and must overcome diverse cellular barriers to cause disease, including the polarized epithelium lining the gastrointestinal tract. Viral infection of a host cell results in a variety of cellular responses that serve to control the viral infection. Once such response is the activation of intracellular innate immune signaling; this results in the production of type I interferon, which signals in an auto- and paracrine fashion to alter the transcriptional profile of a cell to inhibit viral replication. A second response to viral infection is the induction of cell death pathways; as viruses utilize host cell machinery for replication, early cell death of a host cell can result in an abortive infection. Here, I examine the ways in which CVB interfaces with these host cell pathways that affect viral replication. A primary mechanism utilized by CVB for altering host cell pathways is the production of the virally-encoded cysteine protease 3Cpro. 3Cpro is required to process the viral polypeptide but is also known to target cellular protein targets for proteolysis. Here, I identify two cellular proteins targeted for proteolysis by 3Cpro, Unc93b and RIP3, that are involved in the intracellular innate immune signaling and cell death pathways, respectively. I then characterize the roles of these proteins and their cleavage during CVB infection. In summary, I explore the ways in which CVB manipulates its host cell through iii proteolysis of host cell proteins by the virally-encoded protease 3Cpro and find that the balance between virus and host is finely tuned through the activity of this protease. iv TABLE OF CONTENTS PREFACE .................................................................................................................................... XI 1.0 INTRODUCTION ........................................................................................................ 1 1.1 COXSACKIEVIRUS B3 ..................................................................................... 1 1.1.1 Pathogenesis of CVB ....................................................................................... 1 1.1.1.1 History of CVB Pathogenesis ............................................................... 1 1.1.1.2 Route of CVB Infection ........................................................................ 3 1.1.1.3 CVB infection of the heart .................................................................... 4 1.1.1.4 CVB infection of the central nervous system ...................................... 6 1.1.1.5 CVB infection of the pancreas ............................................................. 6 1.1.2 Viral Life Cycle ................................................................................................ 7 1.1.2.1 Viral Entry ............................................................................................. 8 1.1.2.2 Viral Replication ................................................................................... 9 1.1.2.3 Viral Egress ......................................................................................... 10 1.2 CVB INFECTION AND CELL DEATH ........................................................ 11 1.2.1 CVB-Induced Apoptosis ............................................................................... 13 1.2.2 CVB-Induced Necrosis .................................................................................. 15 1.3 CVB INFECTION AND INNATE IMMUNE SIGNALING ......................... 16 1.3.1 TLR-mediated CVB sensing ......................................................................... 18 v 1.3.2 RLR-mediated CVB sensing ......................................................................... 20 1.4 VIRUS-HOST CELL INTERACTIONS DURING CVB INFECTION ...... 21 1.4.1 CVB and host cell translation ....................................................................... 21 1.4.2 CVB and cell death signaling ........................................................................ 22 1.4.3 CVB and innate immune signaling .............................................................. 23 1.5 UNC93B AND TOLL-LIKE RECEPTOR TRAFFICKING ........................ 24 1.6 RIP3-DEPENDENT NECROPTOSIS ............................................................. 26 1.6.1 Cellular mechanisms of necroptosis ............................................................. 27 1.6.1.1 Activation of necroptosis .................................................................... 27 1.6.1.2 Negative regulation of necroptosis ..................................................... 29 1.6.1.3 Necroptosis signaling .......................................................................... 31 1.6.1.4 Necroptosis effector mechanisms ....................................................... 32 1.6.2 Necroptosis and microbial infections ........................................................... 34 1.6.3 Necroptosis in human physiology ................................................................. 36 1.7 AUTOPHAGY ................................................................................................... 37 1.7.1 Mechanisms of Autophagy ............................................................................ 38 1.7.2 Autophagy and CVB infection ..................................................................... 40 2.0 UNC93B INDUCES CELL DEATH AND IS CLEAVED BY CASPASES AND AN ENTEROVIRAL PROTEASE ........................................................................................... 42 2.1 INTRODUCTION ............................................................................................. 42 2.2 RESULTS ........................................................................................................... 45 2.2.1 Expression of Unc93b induces cell death ..................................................... 45 2.2.2 Unc93b is cleaved by caspases ...................................................................... 48 vi 2.2.3 Unc93b is cleaved by the CVB virally-encoded protease 3Cpro ................. 50 2.2.4 Unc93b cleavage does not effect its localization or trafficking .................. 54 2.2.5 Unc93b cleavage does not effect its induction of cell death. ...................... 56 2.3 DISCUSSION ..................................................................................................... 58 3.0 RIP3 IS REQUIRED FOR CVB INFECTION ....................................................... 61 3.1 INTRODUCTION ............................................................................................. 61 3.2 RESULTS ........................................................................................................... 64 3.2.1 RIP3 facilitates CVB infection in intestinal epithelial cells ....................... 64 3.2.2 RIP3 silencing reduces CVB replication prior to viral egress ................... 67 3.2.3 RIP3 is not required for CVB entry into intestinal epithelial cells ........... 68 3.2.4 RIP3 regulates autophagy in intestinal epithelial cells .............................. 69 3.2.5 RIP3 interacts with p62 ................................................................................. 73 3.2.6 The CVB-encoded cysteine protease 3Cpro cleaves RIP3 ........................... 74 3.2.7 3Cpro-mediated cleavage fragments are incapable of inducing necrotic cell death… ........................................................................................................................ 77 3.2.8 The C-terminal fragment of RIP3 generated by 3Cpro cleavage retains its ability to bind p62 ...................................................................................................... 78 3.3 DISCUSSION ..................................................................................................... 81 4.0 CONCLUSIONS ........................................................................................................ 87 4.1 UNC93B AND CELL DEATH ......................................................................... 88 4.2 RIP3 AND CVB INFECTION .......................................................................... 88 4.3 CONCLUDING REMARKS ...........................................................................
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