Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Susan R. Weiss

Abstract

Coronaviruses comprise a large family of viruses within the order Nidovirales containing single-stranded positive-sense RNA genomes of 27-32 kilobases. Divided into four genera (alpha, beta, gamma, delta) and multiple newly defined subgenera, coronaviruses include a number of important human and livestock pathogens responsible for a range of diseases. Historically, human coronaviruses OC43 and 229E have been associated with up to 30% of common colds, while the 2002 emergence of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) first raised the specter of these viruses as possible pandemic agents. Although the SARS-CoV pandemic was quickly contained and the virus has not returned, the 2012 discovery of Middle East respiratory syndrome-associated coronavirus (MERS-CoV) once again elevated coronaviruses to a list of global public health threats. The genetic diversity of these viruses has resulted in their utilization of both conserved and unique mechanisms of interaction with infected host cells. Like all viruses, coronaviruses encode multiple mechanisms for evading, suppressing, or otherwise circumventing host antiviral responses. Specifically, our lab has studied coronavirus interactions with antiviral pathways activated by the presence of cytoplasmic viral double-stranded RNA (dsRNA) such as OAS-RNase L and interferons (IFN). Previous work from our lab demonstrated that the murine coronavirus mouse hepatitis virus (MHV) uses a phosphodiesterase (PDE) to suppress RNase L activation. We have also now shown that additional viruses within Nidovirales encode similar PDEs that suppress RNase L activation in the context of chimeric MHV, and that a PDE encoded by MERS-CoV, the NS4b accessory protein, inhibits RNase L in its native context. I have further shown that MERS-CoV NS4b is a unique PDE with additional functions inhibiting the IFN response, a role dependent on both nuclear localization and its catalytic activity.

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