Abstract

Although autophagy, which is the process by which cells reallocate nutrients and eliminate unwanted materials, has been studied for decades, the connections between autophagy, inflammation, and viral immunity are still under investigation. Our studies focus on two genes: murine Epg5, which is involved in fusion of the autophagosome and lysosome, and C. elegans atg-3, which is important for the elongation of the phagophore. Here, we find that Epg5 mutation protects against enteric viruses including norovirus and rotavirus. We identify IFN- responsive genes as a key alteration and observe that Epg5 mutant mice exhibit substantial alterations in the intestinal microbiota. Surprisingly, germ-free mouse studies indicate that Epg5-associated inflammation of the intestine and the lung is microbiota-independent. Genetic studies support IFN- signaling as the primary mediator of resistance to enteric viruses. In search of a more tractable model system, we discover that a subset of autophagy genes has an antiviral role in Orsay virus infection in C. elegans though Orsay virus infection does not modulate autophagic flux. We also find that re-feeding after starvation limits Orsay virus infection and blocks autophagic flux. Interestingly, we observe that atg-3 mutants phenocopy rde-1 mutants in transcriptional response to infection. Rde-1 mutants have a defect in RNA interference (RNAi), which is the main defense against viral infection in C. elegans. We find that atg-3 mutants do not have a defect in RNAi. In addition, atg-3 mutation affects viral infection at a post entry step. RNA sequencing reveals that atg-3 mutation affects collagen organization pathways, which have recently been identified to have an antiviral role in Orsay virus infection. Together, these data identify novel roles for different autophagy genes in regulating enteric virus infections.

Committee Chair

Megan Baldridge

Committee Members

Carolina Lopez; Siyuan Ding; Stephen Pak; Ta-Chiang Liu; Tim Schedl

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

3-12-2026

Language

English (en)

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Virology Commons

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