Advisor(s)
Kevin Harrod
Committee Member(s)
Anoma Nellore
Carlos Orihuela
Chad Petit
Megan Kiedrowski
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Microbiology
Date of Award
9-11-2025
Abstract
Influenza A Virus (IAV) is commonly complicated by secondary bacterial infections with Streptococcus pneumoniae (Spn), leading to increased morbidity and mortality. Recent work from our lab demonstrates that an IAV-induced loss of cystic fibrosis transmembrane conductance regulator (CFTR) in the airway disrupts the rheostatic properties of the airway surface liquid (ASL). In cystic fibrosis, caused by mutations in the CFTR gene, there is an increase in the bacterial burden of the airway. However, the underlying mechanisms and damage caused by IAV-induced CFTR dysfunction in the airway remains unknown. Using a primary differentiated human bronchial airway epithelial cell culture (HBEC) system, we find that IAV-induced CFTR dysfunction increases susceptibility to Spn via a CFTR-dependent acidification of the ASL. Additionally, we find that IAV induces a robust alteration in both the transcriptional profile and the secreted proteome of the airway epithelium. These findings establish a role for CFTR-dependent disruption of host defense in the airway during IAV. The second chapter of this thesis focuses on defining the mechanism of IAV–induced CFTR dysfunction, and how this increases susceptibility to Spn. IAV and other respiratory viruses induce endoplasmic reticulum (ER) stress and the unfolded protein response, and chemically induced ER stress alone causes a dysregulation of CFTR. Here, we find that IAV–induced ER stress leads to a loss of CFTR activity, and subsequently a dehydration and acidification of the ASL. ER stress alone and during IAV increases Spn, but only in the presence of a functional CFTR. Consistent with this, correction of the pH of the ASL during ER stress reduces Spn. Collectively, this work identifies ER stress alone and during IAV as a source of CFTR dysfunction and a loss of host defense in the airway epithelium. The work presented in this thesis establishes CFTR dysfunction as a primary driver of secondary Spn infections to IAV, defines ER stress as the cause of CFTR dysfunction and characterizes IAV–, CFTR– and ER stress–dependent disruptions in the airway epithelium that diminish host defense. Further, these studies identify the airway epithelium as a central mediator of secondary bacterial infections to IAV.
ProQuest ID
Recommended Citation
Earnhardt, Erin Yepsen, "Influenza A Virus Increases Susceptibility To Streptococcus Pneumoniae By Damaging The Airway Epithelium" (2025). All ETDs from UAB. 7382.
https://digitalcommons.library.uab.edu/etd-collection/7382
