Individualized Cellular Response To Influenza-A Infection

Authors

• Abel Lopez, University of Alabama at Birmingham

Advisor(s)

Kevin Harrod

Committee Member(s)

David Crossman
Ryan Melvin

School

Joint Health Sciences (Interdisciplinary)

Document Type

Thesis

Department (new version)

Genetics

Date of Award

9-9-2024

Abstract

Influenza A Virus (IAV) presents a significant threat to global health, causing millions of severe cases and substantial mortality annually. This study uses single-cell RNA sequencing to investigate the individualized cellular response to IAV infection in human bronchial epithelial cells (HBECs). We employed air-liquid interface (ALI) cultures to model the respiratory epithelium and differentiated HBECs into basal, ciliated, secretory (goblet/club), and rare cell types (Ionocytes). Following IAV infection, we analyzed transcriptional changes across these cell types, focusing on differential gene expression and pathway activation. Our results highlight the variability in IAV infection and the distinct cellular responses. Ciliated cells, the most susceptible to infection, exhibited a robust interferon response and activation of RNA splicing and protein folding pathways at low infection levels. However, high infection levels resulted in downregulated transcriptional activity, likely due to ER stress and the unfolded protein response (UPR). Basal cells showed consistent upregulation of antiviral and cilia regeneration pathways, emphasizing their role in maintaining epithelial integrity and mucociliary clearance. Secretory cells responded dynamically, with significant transcriptional changes and downregulation of RNA splicing and translation pathways, suggesting a strategy to limit viral replication. Rare cell types, such as ionocytes, demonstrated an adaptive response, initially upregulating ribosomal and ATP synthesis pathways at low infection levels but shifting towards stress management and resource conser vation under higher viral loads. Gene set enrichment analysis (GSEA) revealed the critical role of interferon signaling, viral modulation, and cilia-related pathways in the host defense against IAV. This study underscores the importance of considering cell type-specific responses in understanding IAV pathogenesis and developing therapeutic interventions. The differential activation of antiviral mechanisms, cellular stress responses, and repair pathways across HBECs provides valuable insights into the cellular dynamics of IAV infection. These findings pave the way for targeted therapies that enhance host defense mechanisms and mitigate the impact of IAV on the respiratory epithelium.

ProQuest ID

https://proquest.com/docview/3101861050