Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Susan R. Weiss

Abstract

Murine hepatitis virus (MHV) infection activates the potent antiviral oligoadenylate synthetase-endoribonuclease latent (OAS-RNase L) pathway in myeloid-derived cells of the liver and brain but not in other cell types in these organs. Canonically, it is thought that upregulation of Oas transcription by type I interferon (IFN) during virus infection is needed to activate the pathway. However, MHV induces IFN and upregulate OASs only late in infection, after RNase L has already been activated. The objective of this thesis work was to determine what role interferon and OAS play in RNase L activation. For this purpose, bone marrow derived macrophages (BMM) were used that were either fully competent to respond to and secrete IFN (WT B6), unable to secrete IFN (Ifih1-/-), or not capable of IFN signaling (Ifnar1-/-). It was found that basal mRNA expression levels of Oas1a, Oas2, and Oas3 in naïve mice were significantly higher in the liver than in the brain and in myeloid-derived versus non-myeloid derived cells. Furthermore, activation of RNase L did not require virus-induced IFN, but rather correlated with adequate levels of basal Oas gene and protein expression, maintained by basal IFN signaling. This suggests that basal levels of OAS might influence the host’s ability to activate RNase L and restrict MHV infection in an organ-specific and cell type-specific manner. Data herein demonstrate that myeloid cells are pre-armed with high basal levels of OAS, sufficient to allow activation of RNase L upon sensing dsRNA early in infection before interferon signaling develops. This limits virus replication and spread, thus sparing non-myeloid neighboring cells from infection. Together, these studies have helped define the increasingly complex interactions between MHV and the type I IFN response.

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