Regulation of Pseudomonas aeruginosa Chronic Infection Phenotypes Pubblico

Abstract

Pseudomonas aeruginosa is an opportunistic bacterial pathogen with the ability to persist in many complex environments. The resilient nature of P. aeruginosa supports rapid adaption and long-term survival of this bacterium in stressful niches. This is especially true when it comes to the establishment of chronic lung infections in people with cystic fibrosis (CF). The most significant manifestation of CF disease occurs in the lungs where there is increased inflammation, thick mucus accumulation, and reduced clearance of inhaled bacteria. As a result, lung damage and persistent bacterial infections are the leading cause of morbidity and mortality in this population. Up to 50% of people with CF in the United States culture positive for P. aeruginosa, making it one of the most predominant pathogens. 

The persistence, survival, and adaption to this unique lung ecosystem is reflected by the expression of unique phenotypes. These phenotypes are collectively termed the "chronic infection phenotype" and distinguishes chronic CF isolates from most other types of infections and environmental sources. This is because CF isolates are often mucoid, due to the overproduction of the exopolysaccharide alginate, and have defective lipopolysaccharide O antigen production. The studies presented here contribute to our understanding of the regulation of chronic infection phenotypes in P. aeruginosa. This includes the discovery of a novel feedback mechanism linking alginate biosynthesis to alginate promoter expression as well as the characterization of the regulon of a histone-like protein once thought to be involved in regulating alginate production. 

Control of alginate production is regulated primarily by the sigma factor AlgT. Experiments performed here also reveal that overproduction of AlgT is lethal to mucoid strains of P. aeruginosa and that very long O antigen production is regulated at the genetic level by the AlgT-dependent transcription factor AmrZ. Understanding the regulation of these chronic phenotypes will elucidate mechanisms that are important for the establishment of a long-term P. aeruginosa lung infection and ultimately provide an opportunity for intervention. Preventing P. aeruginosa from chronically adapting to the CF lung environment could provide a better outcome for people who are infected.

Table of Contents

DISTRIBUTION AGREEMENT

APPROVAL SHEET

ABSTRACT COVER PAGE

ABSTRACT

COVER PAGE

TABLE OF CONTENTS

LIST OF FIGURES

LIST OF TABLES

Chapter 1. An introduction to Pseudomonas aeruginosa, an adaptable bacterium, 1

Chapter 2. The AlgP histone-like protein regulon is distinct in nonmucoid and mucoid Pseudomonas aeruginosa and does not include alginate biosynthesis genes, 27

Chapter 3. Remodeling of O antigen in mucoid Pseudomonas aeruginosa via transcriptional repression of wzz2, 58

Chapter 4. Overexpression of the AlgT sigma factor is lethal to mucoid Pseudomonas aeruginosa, 99

Chapter 5. The alginate biosynthesis operon is autoregulated in Pseudomonas aeruginosa through a positive-feedback loop involving the AlgT sigma factor, 117

Chapter 6. Discussion and future directions for the studies of chronic phenotypes in Pseudomonas aeruginosa, 141

Appendix 1. Construction of reporters to test the temperature regulation and single cell 

dynamics of wzz1 and wzz2 in Pseudomonas aeruginosa, 148

Appendix 2. Generation and phenotypic analysis of Pseudomonas aeruginosa wzz mutants, 173

Appendix 3. Nucleotide duplications in algT cause nonmucoid reversion, 195

References, 206

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Microbiology & Molecular Genetics
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Microbiology Health Sciences, Pathology
Parola chiave	cystic fibrosis chronic infection Pseudomonas aeruginosa
Committee Chair / Thesis Advisor	Joanna Goldberg, Emory University
Committee Members	William Shafer, Emory University David Weiss, Emory University Charles Moran, Emory University Philip Rather, Emory University

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