Striking a Balance: Analysis of the Protective and DestructiveEffects of Innate Immunity in Response to the A/E PathogenCitrobacter rodentium Public

Abstract

Attaching and effacing (A/E) pathogens such as enteropathogenic Escherichia coli (EPEC) and Citrobacter rodentium adhere to intestinal epithelia and destroy absorptive microvilli. In mice, C. rodentium breach the intestinal epithelial barrier, leading to colitis via vigorous inflammation. Ultimately, a protective antibody response clears the infection. Here I explore the regulatory mechanisms that orchestrate a balanced innate immune response that facilitate both destructive effects, such as inflammation, and protective effects during a C. rodentium infection. More specifically, I demonstrate that the signaling cascades activated by the type I IL-1 receptor and MyD88, a signaling adaptor protein utilized by several innate immune receptors including TLRs and IL-1R, protect mice from lethal intestinal damage induced by C. rodentium. Interestingly, although the intestinal damage prevented by MyD88 signaling is associated with many complex and interrelated phenotypes including induction of epithelial repair, neutrophil recruitment, and control of pathogen load, IL-1R signaling appears to only regulate sensitivity of intestinal epithelia to damage caused by C. rodentium. Finally, I show that a slow growing variant of C. rodentium induces equally low levels of disease in wild type and MyD88-/- mice, suggesting that the increased intestinal damage seen in infected MyD88-/- animals is pathogen- induced, rather than host-induced. Together these studies indicate that IL-1R, TLR, and MyD88 signaling mediate a balanced innate immune response in which the protective effects outweigh the destructive effects during infection with C. rodentium.

Table of Contents

Document Outline Table of Contents Chapter 1 Chapter 2 Chapter 3 Chapter 4 CHAPTER 5

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Microbiology & Molecular Genetics
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Microbiology
Mot-clé	Intestinal Pathogens Innate Immunity
Committee Chair / Thesis Advisor	Kalman, Daniel, Emory University
Committee Members	Shafer, William M, Emory University Sherman, Melanie, Emory University, Pathology Department Speck, Sam, Emory University Williams, Ifor R, Emory University

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