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Investigations Into Antiviral Microglia Activation During West INVESTIGATIONS INTO ANTIVIRAL MICROGLIA ACTIVATION DURING WEST NILE VIRUS INFECTION OF THE CENTRAL NERVOUS SYSTEM by EAMON DRAKE QUICK B.S, Brown University, 2007 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirements for the degree of Doctor of Philosophy Neuroscience 2017 This thesis for the Doctor of Philosophy degree by Eamon Drake Quick has been approved for the Neuroscience Program by Wendy Macklin, Chair Kenneth L. Tyler, Advisor Diego Restrepo J. David Beckham Laurel Lenz Penny Clarke, Co-Advisor Date: December 15th, 2017 ii Quick, Eamon Drake (PhD, Neuroscience) Investigations into Microglia Activation During West Nile Virus Infection Thesis directed by Kenneth L. Tyler ABSTRACT Microglia are the resident innate immune cells of the central nervous system (CNS), and are thought to have important roles in the detection of noxious stimuli and the regulation of inflammatory events within the CNS parenchyma. For certain diseases, the evidence for microglia contributions to pathogenesis and inflammatory responses are lacking, and this is especially true for neuroinvasive West Nile virus (WNV) infections. WNV infections are the leading cause of acute viral encephalitis epidemics and related illnesses in North America, with a significant rate of mortality observed in clinical cases. Studies of experimental WNV infection in mice have established the key role played by both innate and adaptive immune responses in clearing virus from the CNS and limiting neuronal death. Neuroinflammation of peripheral immune cells is a vital component of WNV clearance, but any role for microglia to initiate immune responses or to act as effector immune cells is unclear. The present thesis details work towards the establishment and utilization of unique model systems to investigate microglia activation in response to WNV infection, and the potential consequences of this activation. An ex vivo slice culture model system for studying WNV infection was used to determine the potential for innate immune activation by microglia, with many examples of morphological changes, chemotaxis, and phagocytosis. Minocycline was administered to WNV-infected slice cultures to inhibit the pro- inflammatory activation of microglia, with notable reductions in relevant pro-inflammatory cytokines/chemokines and elevations in anti-inflammatory cytokines/chemokines that could iii be attributed to microglia production. Finally, an in vivo microglia depletion model for WNV infection was used through the administration of the CSF1R kinase inhibitor PLX5622. WNV infection in mice treated with PLX5622 lead to decreased survival and significantly increased WNV infection of the CNS compared to control mice, with deficits in gene expression for CCL5 and TREM2 highlighting the ability to compare the results between the slice culture and in vivo model systems. Overall, this study has made significant gains in the understanding of how microglia can act as effector immune cells during WNV infection and their importance for necessary antiviral responses. The form and content of this abstract are approved. I recommend its publication. Approved: Kenneth L. Tyler iv Dedicated to my parents v ACKNOWLEDGEMENTS I would like to thank the Kenneth L. Tyler lab for allowing me the space, time, and resources to address experiments that had little to no precedent in the manner I thought best. The experience has been extremely educational. Many thanks to the staff of the animal facilities for maintaining healthy mice for our experiments, allowing us to work with dangerous viruses on the premises, and monitoring the day-to-day work that allowed us the ability to do our research. Special thanks to Plexxikon for providing us with PLX5622 per the material transfer agreement. This research would not have been possible without funding from several sources. The Tyler lab was funded by the National Institute of Health (NIH) grants R01 NS076512 and R21/R33 AI101064, as well as a VA merit grant. Additional funding support for myself came from T32 HD041697-12 (2012-2013) and T32 AI052066-13 (2015-2016). The Tyler lab IACUC protocol number was B-34716(03)1E. A final thanks goes to S. Rock Levinson, who taught me much about sample and antibody preparation that contributed greatly to the work in this dissertation. Many hours were spent on his Nikon confocal scope which he allowed me to use as my personal scope for several years and allowed me to take amazing images of microglial phagocytosis. vi TABLE OF CONTENTS CHAPTER I. INTRODUCTION Microglia During Development and Homeostasis…….…………………1 Microglia During Disease and Viral Infections………….………………2 West Nile Virus (WNV) Neuroinvasive Disease…………..…………….6 Microglia and WNV: Project Outline……………………………………9 II. AIM 1: MICROGLIA ACTIVATION IN A SLICE CULTURE MODEL SYSTEM OF WEST NILE VIRUS INFECTION OF THE CENTRAL NERVOUS SYSTEM Introduction……………………………………………….…………….13 Materials and Methods………………………………………………….15 Results…………………………………………………………………..22 Discussion...………………………………………………………….…42 III. AIM 2: MINOCYCLINE ADMINISTRATION AND MICROGLIA INHIBITION IN A SLICE CULTURE MODEL SYSTEM OF WEST NILE VIRUS INFECTION OF THE CENTRAL NERVOUS SYSTEM Introduction………………………………………………………….…50 Materials and Methods…………………………………………………52 Results………………………………………………………………….54 Discussion...……………………………………………………………63 vii IV. AIM 3: PLX5622 ADMINISTRATION AND MICROGLIA DEPLETION DURING WEST NILE VIRUS INFECTION IN VIVO Introduction…………………………………………………...…….…71 Materials and Methods……………………………………...…………75 Results…………………………………………………...…………….78 Discussion...……………………………………………………...……88 V. CONCLUSIONS AND FUTURE DIRECTIONS. Microglia Phagocytosis and Antiviral Activity During WNV Infection of the Central Nervous System….…….…………………………………...…92 Future Directions: Slice Culture Model System….……………...…….94 Future Directions: PLX5622 Model System of WNV Infection…..…..95 REFERENCES…………………………………………………….…………..99 APPENDIX……………………………………………………………………115 viii CHAPTER I INTRODUCTION Microglia During Development and Homeostasis Within the mammalian central nervous system (CNS) reside the cells that control the body as a whole. The primary functional cells of this control mechanism are neurons, which are a largely post-mitotic population that require high levels of specialized support both from their environment and the support cells around them. The environment of neurons is maintained by the blood-brain barrier (BBB), which primarily serves to protect the neurons from infection, cytotoxic inflammatory cells, and noxious components in the blood. Within the BBB is the parenchyma of the CNS, which includes neurons and the support cells that assist neuronal function, generally known as glia. The three major glia cell types in the CNS are astrocytes, oligodendrocytes, and microglia. In addition to providing trophic support, each of these cell types perform specific functions to create a proper environment for neuronal function. Astrocytes maintain the blood brain barrier and aid in the clearance and reuptake of neurotransmitters from the cerebrospinal fluid (CSF). Oligodendrocytes myelinate axons and provide structural support for neurons. Microglia provide innate immune surveillance and are the primary phagocyte of the CNS. When the nervous system begins development, the precursor cells of the neuroectoderm that give rise to neurons also are the ancestral source of astrocytes and oligodendrocytes. Microglia originate from macrophage precursors in the yolk sac (Ginhoux 2010, Schulz 2012, Alliot 1999, Prinz and Mildner 2011), and then later migrate to the developing CNS to provide support via clearance of apoptotic cells (Marin-Teva 2004, 1 Wakselman 2008, Paolicelli 2011). Subsequent to the arrival of microglia to the developing CNS, the blood-brain barrier begins to form and eventually encompasses the CNS parenchyma, closing it off from the rest of the body. Microglia form a self-sustaining population that is not renewed by peripheral macrophages or other blood-borne cells (Hoeffel 2012). This distinction makes microglia particularly different from peripherally-derived macrophage populations, including not only other tissue resident macrophages (e.g., Langerhans cells in the skin) but also from other CNS-related macrophages, including perivascular and meningeal macrophages (Jung and Schwartz 2012, Neumann and Wekerle 2013, Bessis 2007). These considerations highlight the fact that microglia are highly attuned to function within the CNS environment, and have a range of responsibilities that differ substantially from their peripheral counterparts. Under homeostatic conditions, microglia have a much different set of responsibilities compared to peripheral macrophages and resident tissue innate immune cells. Microglia maintain their own niche spaces within the CNS and are uniformly distributed (Rezaie and Male 2002). Thin cellular processes extend out from microglia in all directions and survey the microenvironment in a highly dynamic manner (Nimmerjahn 2005, Davalos 2005). In addition to their surveillance functions, microglia have been shown to perform a process known as synaptic pruning, where synapses are removed from the dendrites of neurons and thought to be a part of the broader paradigm of neuronal plasticity (Schafer 2012, Tremblay 2010). Microglia During Disease and Viral Infections As the resident innate immune cells of the CNS, microglia have the responsibility to detect noxious stimuli that pose a threat to the nervous system.
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