All ETDs from UAB

Advisory Committee Chair

Casey T Weaver

Advisory Committee Members

David E Briles

David D Chaplin

Charles O Elson

John F Kearney

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Enteropathogenic strains of Escherichia coli are a major public health concern, causing diarrhea and mortality particularly among infants and children in developing countries. Citrobacter rodentium is a murine intestinal pathogen that models pathogenic E. coli infection. Both innate and adaptive immune cells contribute to the clearance of C. rodentium. In particular, B cells and CD4+ T cells but not CD8+ T cells are required for protection during a primary infection with C. rodentium. In addition, T cell-dependent antibody responses are required for clearance. Th17 cells are a major CD4+ T cell population that accumulates in the large intestine during C. rodentium infection. Th17 cells are known to produce several pro-inflammatory cytokines including, interleukin-17 (IL-17), interleukin-21 (IL-21), and interleukin-22 (IL-22) that are crucial to promote host defense against extracellular pathogens. Interestingly, we found that innate cells are an abundant source of IL-22 prior to day 8 of infection; whereas, later, CD4+ T cells are the dominant source of IL-22 required for host defense against C. rodentium. In addition, cells that produce IL-22 alone without co-production of IL-17A (Th22 cells) are relatively more protective than Th17 cells in this infection model. Interleukin-6 (IL-6) is a potent inducer of IL-21 and IL-22. Since C. rodentium in-fection was lethal in both Il6–/– and Il22–/– mice, we examined whether IL-21 was also required for host defense. Il21–/– mice did not succumb to C. rodentium infection; however, they had a significant impairment in their ability to resolve infection with this pathogen. Using a novel dual IL-21 reporter/conditional knock-out mouse (Il21hCD4/fl), we find that CD4+ T cells and not innate cells are the dominant source of IL-21 during C. rodentium infection. In addition, we demonstrate that CD4+ T cell-derived IL-21 alone is sufficient for a normal humoral response and rapid clearance of C. rodentium. Together, these studies highlight the contributions of innate and adaptive cytokine-producing cells in host defense against C. rodentium. Whereas IL-22 mediates protection via both innate and adaptive cells, IL-21-dependent protection is primarily a feature of the adaptive immune system.

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