DOI

10.17077/etd.5ret-l5fa

Document Type

Dissertation

Date of Degree

Spring 2019

Access Restrictions

Access restricted until 07/29/2020

Degree Name

PhD (Doctor of Philosophy)

Degree In

Immunology

First Advisor

Perlman, Stanley

Second Advisor

Houtman, Jon

First Committee Member

Mangalam, Ashutosh

Second Committee Member

Harty, John

Third Committee Member

Badovinac, Vladimir

Abstract

Viral infection of the central nervous system is complicated by the mostly irreplaceable nature of neurons, as the loss of neurons has the potential to result in permanent damage to brain function. However, whether neurons or other cells in the CNS sometimes survive infection and the effects of infection on neuronal function are largely unknown. To address this question, I used the rJHM strain (rJ) of mouse hepatitis virus, (MHV), a neurotropic coronavirus, which causes acute encephalitis in susceptible strains of mice. To determine whether neurons or other CNS cells survive acute infection with this virulent virus, I developed a recombinant JHMV that expresses Cre recombinase (rJ-Cre) and infected mice that universally expressed a silent (floxed) version of tdTomato. Infection of these mice with rJ-Cre resulted in expression of tdTomato in host cells. The results showed that some cells were able to survive the infection, as demonstrated by continued tdTomato expression after virus antigen could no longer be detected. Most notably, interneurons in the olfactory bulb, which are known to inhibit other neurons, represented a large fraction of the surviving cells. The results described in this thesis indicated that some neurons are resistant to virus-mediated cell death and provide a framework for studying the effects of prior coronavirus infection on neuron function.

Another aspect of this thesis concerns the role of microglia in virus infections. Recent findings have highlighted roles for microglia in orchestrating normal development and refining neural network connectivity in the healthy central nervous system (CNS). Microglia are not only vital cells in maintaining CNS homeostasis, but also respond to injury, infection, and disease, by undergoing proliferation, and changes in transcription and morphology. Understanding the specific role of microglia in responding to viral infection is complicated by the presence of non-microglial myeloid cells with potentially overlapping function in the healthy brain, and by the rapid infiltration of hematopoietic myeloid cells into the brain in diseased states. Here, I used a CSF1R inhibitor that depletes microglia to examine the specific roles that microglia play in response to infection with a neurotropic coronavirus (MHV). My results show that microglia were required during the first days post infection to limit MHV replication, subsequent tissue damage and lethality. Additionally, microglia depletion resulted in ineffective T cell responses. These results reveal nonredundant, critical roles for microglia in the early innate and virus-specific T cell responses and for subsequent host protection from viral encephalitis.

Overall these studies provide new insight into cells that survive MHV infection and into the role microglia play in the immune response to MHV. Specifically, many neurons, especially interneurons of the olfactory bulb survive MHV infection and microglia play a role in both the innate and adaptive immune response to viruses.

Pages

x, 97 pages

Bibliography

Includes bibliographical references (pages 87-97).

Copyright

Copyright © 2019 Dorthea L. Wheeler

Available for download on Wednesday, July 29, 2020

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