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Title:Modulation of FOXA2-Mediated Airway Mucus Homeostasis by Pseudomonas aeruginosa Lipopolysaccharides
Author(s):Mathew, Anita
Contributor(s):Lau, Gee
Pseudomonas aeruginosa
mucus secretion
Abstract:Cystic fibrosis (CF) is a major genetic disorder affecting Caucasian populations. Mutations in the CFTR chloride channel gene cause osmotic imbalance and hyperabsorption of airway surface liquid, which thickens and prevents mucus clearance. Excessive mucus and failure in clearance create a thriving niche for microbial pathogens. Among the most significant pathogens is Pseudomonas aeruginosa (PA), a major ESKAPE pathogen that chronically infects CF airways. Repeated cycles of PA infection exacerbate mucus hypersecretion and airway obstruction. My undergraduate research advisor Dr. Gee Lau's laboratory has previously shown that multiple PA virulence factors, including pyocyanin, lipopolysaccharides (LPS), flagellum, and alginate are capable of causing mucus hypersecretion in airways. PCN induces excessive mucus within airways by inactivating FOXA2, a key transcription factor that regulates mucus homeostasis. The mechanisms by which LPS induce mucus hypersecretion in the CF airways are poorly understood. During chronic colonization of CF airways, PA has tendency to select for strains with mutated LPS, especially in the O-antigen. The contribution of mutated LPS to mucus hypersecretion is unknown. In this study, I investigated and compared the ability of wild-type LPS (wtLPS) versus mutated LPS (mtLPS) of PA to induce mucus hypersecretion in vivo by using a mouse model of exposure, as well as in vitro by using a human airway epithelial cell line 16HBE. The results showed that wtLPS induces mucus hypersecretion by inactivating FOXA2. In contrast, mtLPS deficient either in A-Band O-antigen and/or B-Band O-antigen have reduced ability to inhibit FOXA2 expression and induce mucus biosynthesis. These results suggest that wtLPS is an inducer of mucus hypersecretion in the initial stages of CF infection. In contrast, mtLPS expressed by various mutant PA strains is not a major contributor to mucus hypersecretion in chronic CF airways.
Issue Date:2017
Genre:Dissertation / Thesis
Rights Information:Copyright 2017 Anita Mathew
Date Available in IDEALS:2017-05-15

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