Deciphering the mechanism of foxa2 inactivation by respiratory pathogens in chronically diseased lungs

Choi, WooSuk

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https://hdl.handle.net/2142/108688 Copy

Description

Title

Deciphering the mechanism of foxa2 inactivation by respiratory pathogens in chronically diseased lungs

Author(s)

Choi, WooSuk

Issue Date

2020-07-14

Director of Research (if dissertation) or Advisor (if thesis)

Lau, Gee W.

Doctoral Committee Chair(s)

Lau, Gee W.

Committee Member(s)

• Wilson, Brenda A.
• Yang, Jing
• Witola, William H.

Department of Study

Pathobiology

Discipline

VMS - Pathobiology

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Airway epithelial cells
• FOXA2
• mucin hypersecretion
• microbial infection

Abstract

FOXA2 is an evolutionally conserved transcription factor of forkhead box (FOX) family. FOXA2 regulates airway mucus homeostasis and acts as a transcription repressor of airway mucin5ac (MUC5AC) and mucin5b (MUC5B) genes. In diseased human and other mammalian airways, FOXA2 is inactivated in both club cells and ciliated cells, resulting in the differentiation of these pluripotent airway cells into the mucin secreting goblet cells. Mucin-containing mucus layer protects airways from inhaled microbes and irritants. Albeit its protective roles, excessive mucus secretion, accumulation and failure in clearance result in pathophysiologic conditions, especially in muco-obstructive chronic lung diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), primary ciliary dyskinesis (PCD), bronchitis and bronchiectasis. Because accumulated mucus provides a niche environment of microbes to thrive, muco-obstructive lungs are especially vulnerable to infection by microbial pathogens. Pseudomonas aeruginosa is an important bacterial pathogen in chronically diseased airways, especially dominant in CF and advanced stages of COPD. Pyocyanin is a redox-active virulence factors secreted copiously in CF and COPD airways by P. aeruginosa, and is a major inducer of mucus hypersecretion. Among the fungal pathogens, Blastomyces dermatitidis is a causative agent of acute respiratory distress syndrome (ARDS), which is accompanied by excessive mucus production in infected airways. β-glucan is a conserved component of all fungal cell wall that induces inflammatory responses. In this study, we used a combination of human primary cells, diseased lung tissues and mouse models to test the hypotheses that FOXA2 is a major target of inactivation by microbial pathogens, and a potential therapeutic target against mucin hypersecretion in chronically diseased lungs. Furthermore, we examined the mechanisms by which P. aeruginosa and B. dermatitidis, as well as their virulence factors pyocyanin and β-glucan, respectively, induced mucus hypersecretion. Our results indicate that FOXA2 is a conserved target of inactivation by both P. aeruginosa and B. dermatitidis and their virulence factors. Mechanistic studies revealed that these pathogens induced either or both STAT6 and EGFR signaling pathways that antagonized the expression of FOXA2. Furthermore, we showed that both incretin mimetics and thiazolidinediones drugs, prescribed to diabetes mellitus 2 patients, are strong agonists of FOXA2, by activating the glucagon-like peptide-1 receptor (GLP-1R)-mediated signaling that normalizes mucin expression and improved the clearance of P. aeruginosa. In summary restoration of FOXA2 function inactivated by bacterial and fungal pathogens with incretin mimetics and thiazolidinediones may offer potent therapeutic avenue to reduce excessive mucus in chronic airway diseases.

Graduation Semester

2020-08

Type of Resource

Thesis

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http://hdl.handle.net/2142/108688

Copyright and License Information

Copyright 2020 WooSuk Choi

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