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Access Type

WSU Access

Date of Award

January 2018

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Anatomy and Cell Biology

First Advisor

Susmit Suvas

Abstract

The ability of herpes simplex virus 1 (HSV-1) to establish a lifelong infection in neurons of the trigeminal ganglion (TG) make it a constant public health threat. Viral reactivation from its latent state is currently the leading cause of viral induced blindness in the United State, as well as the leading cause of herpes simplex encephalitis. Unfortunately, how the virus is able to both establish and maintain its latent state in the TG is not well understood. The purpose of this work was to better understand how neuropeptide signaling through neurokinin receptors, as well as how satellite glial cells (SGCs) in the TG, affect the establishment and maintenance of HSV-1 latency.

Our results demonstrate that loss of NK1R-/- signaling in the mouse model leads to an increase in corneal lymphatics, which was found to correlate to increased levels of IFNγ produced by CD8 T cells of the draining lymph node (DLN) and increased T cell response in the TG. This increase in immune response was associated with a decrease in viral DNA in the TG during HSV-1 latency establishment. However, the changes in immune response were not observed in NK1R antagonist treated mice. In regard to the maintenance of HSV-1 latency, our work found that NK1R-/- led to increased levels of latency associated transcript in the TGs of latently infected mice, which correlated with a decrease in viral reactivation. Similar decrease in viral reactivation were identified in NK1R and NK3R antagonist treated mice, but no changes in viral reactivation were detected when both receptors were inhibited. We therefore conclude that partial loss of neurokinin receptor signaling in the TG is beneficial to the maintenance of the HSV-1 latent state.

Further, our work focused on understanding the role of SGCs during the maintenance of HSV-1 latency. We demonstrate that when cultured in the presence of antigenic peptide, SGCs are able to present antigen to CD4 T cells, leading to their proliferation. We thus describe for the first time that SGCs are able to function as a non-professional antigen presenting cell. We therefore conclude that during latent HSV-1 infection, SGCs are capable of stimulating CD4 T cells in the TG, leading to an upregulation of inflammatory cytokines that aid in the host response to maintain HSV-1 latency. In total, this work demonstrates that the localized cellular response in the TG during HSV-1 infection plays a critical role in controlling viral latency.

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