Abstract

Rotavirus (RV) is a non-enveloped, double-stranded RNA virus that infects mature intestinal epithelial cells (IECs) and induces diarrhea and gastroenteritis in young mammals, including humans. Meanwhile, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, is mostly regarded as a respiratory virus but also infects IECs, which might explain the gastrointestinal symptoms observed in COVID-19 patients. In the first study, we conducted a small-molecule inhibitor screen of about 200 molecules against SARS-CoV-2 and discovered the broad antiviral activities of JIB-04, a molecule formerly known as an anti-tumor agent, which also inhibits the infection of other viruses including RV and enteric coronaviruses. Additionally, we established how RV induces diarrhea in the absence of viral replication in neonatal mice, showing that sensing of double-stranded RNA in IECs triggers a type III interferon response and water malabsorption. Lastly, we explored the potential RV antagonism of gasdermin D, which is the final effector of the inflammasome pathway and plays an important role in the host innate immune response against RV. Overall, this dissertation covers enteric viral pathogenesis in both fundamental and translational aspects, highlighting host and viral factors that could be targeted for further therapeutic development.

Committee Chair

Siyuan Ding

Committee Members

Gabriel Mbalaviele; Marco Colonna; Megan Baldridge; Michael Diamond; Michael Holtzman

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

5-2-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0002-7204-397X

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Available for download on Friday, April 30, 2027

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Biology Commons

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