Defensive Programs of the Human Airway Epithelium Against Rhinovirus Infection

Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Immunobiology

First Advisor

Foxman, Ellen

Abstract

Rhinovirus (RV) is the most frequent cause of common colds, but also a major cause of respiratory distress in high-risk groups (e.g. smokers and asthmatics). The molecular mechanisms leading to the wide range of infection outcomes are not fully understood. Epithelial cells from highly susceptible patient groups exhibit attenuated interferon (IFN) responses, suggesting that the activity of this key antiviral defense pathway contributes to the range of outcomes. Taking advantage of single cell RNA sequencing (scRNA Seq) in organotypic model of the human airway epithelium, we investigated innate anti-viral immune responses of nasal and bronchial epithelial cells to RV. We showed that differential engagement of innate immune signaling pathways mediated by IRF3 and NLRP1 alters the inflammatory responses of nasal epithelial cells. In the intact epithelium, IFN response restricts the infection to <2% of cells. Inhibiting IFN response increases viral infection to >30% of cells and leads to a distinct NF-κB- and NLRP1-dependent pro-inflammatory response with mucus hyperproduction, neutrophil chemokine production and IL-1 release. Blocking both IFN and NF-κB responses leads to transcriptional signatures of integrated stress response and squamous trans-differentiation. In the bronchial epithelium, we explored the mechanism of viral interference between RV and SARS-CoV-2 using scRNA Seq. We showed that bystander cell IFN response induced by RV blocks subsequent SARS-CoV-2 infection. Lastly, we developed and applied new bioinformatics approach CINEMA-OT to identify synergistic effect of RV infection and cigarette smoke, an environmental factor associated with worse outcomes. Together, our results elucidate molecular mechanisms leading to distinct host responses to RV infection and provide a new understanding of RV pathogenesis.

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