Author ORCID Identifier

https://orcid.org/0000-0003-3532-928X

Semester

Summer

Date of Graduation

2025

Document Type

Dissertation (Campus Access)

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Ivan Martinez

Committee Member

Mariette Barbier

Committee Member

Timothy Driscoll

Committee Member

Gangqing Hu

Committee Member

Jennifer Franko

Committee Member

Aaron Robart

Abstract

Since its emergence, COVID-19—caused by the novel coronavirus SARS-CoV-2—has affected millions globally and led to over 1.2 million deaths in the United States alone. This global impact, coupled with the emergence of five new human coronaviruses over the past two decades, underscore es the urgency of understanding their pathogenic mechanisms at the molecular level—not only for managing the current pandemic but for preparing for future outbreaks. Small non-coding RNAs (sncRNAs) critically regulate host and viral gene expression, including antiviral responses. Among the molecular regulators implicated in antiviral defense, the microRNA-processing enzyme Drosha has emerged as a particularly intriguing factor. In addition to its canonical role, Drosha also exerts a non-canonical, interferon-independent antiviral function against several RNA viruses. We observed a striking shift in Drosha isoform expression following infection with multiple SARS-CoV-2 variants. This shift was absent following treatment with the viral mimetic poly(I:C) or infection with other RNA viruses, including the non-severe coronaviruses HCoV-OC43 and HCoV-229E. We also identified a distinct alteration in Drosha’s cellular localization post SARS-CoV-2 infection. Moreover, Drosha ablation led to reduced expression of SARS-CoV-2 genomic and sub-genomic targets.

While the cytoplasmic localization and presence of alternative Drosha isoforms have been well characterized under various cellular conditions, their relevance during SARS-CoV-2 infection remains unexplored. Upon infection, Drosha undergoes proteolytic cleavage and translocates to the cytoplasm. Functionally, this cytoplasmic shift appears to be significant, as Drosha depletion results in reduced expression of several key SARS-CoV-2 genomic and sub-genomic targets. This dissertation not only elucidates a novel aspect of Drosha’s antiviral role but also advances our understanding of SARS-CoV-2 host–pathogen interactions, details potential therapeutic avenues for future human coronavirus infections.

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