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UBC Theses and Dissertations

Host and pathogen regulation of intestinal epithelial inflammatory responses during bacterial infections Sham, Ho Pan


The attaching and effacing (A/E) bacterial pathogen enteropathogenic Escherichia coli (EPEC), targets the intestinal epithelial cells (IEC) lining the gastrointestinal tract, causing severe diarrhea and potentially death. Although IEC express Toll like receptors (TLRs), they are hypo-responsive to most bacterial products, thereby preventing overt inflammatory responses against commensal bacteria. Single Ig IL-1-Related Receptor (SIGIRR) is a negative regulator of interleukin (IL)-1 and TLR expressed by IECs. Its expression by IEC may limit their ability to respond to invading pathogens, potentially increasing host susceptibility to infection. To address whether SIGIRR expression influences host defense against enteric pathogens, Sigirr deficient (-/-) mice were infected with the mouse adapted A/E pathogen Citrobacter rodentium. Sigirr -/- mice responded with accelerated IEC proliferation, and strong pro-inflammatory and antimicrobial responses in this study. Yet, they were highly susceptible to infection. Exaggerated IEC response of Sigirr -/- mice were primarily dependent on IL-1R signaling leading to the rapid and dramatic loss of competing commensal microbes from the infected intestine. Thus, SIGIRR promotes commensal-based resistance to pathogen colonization despite limiting IEC responses to infection. Besides the host, A/E pathogens also actively suppress IEC inflammatory and anti-microbial responses using a type 3 secretion system to deliver bacterial effector proteins into infected IEC. To identify these effector(s), I tested an array of EPEC mutants and identified that non-LEE encoded effector (Nle)C suppressed the release of the chemokine IL-8 from infected IEC in vitro. NleC localized to EPEC-induced pedestals and inhibited both NF-ΚB and p38MAP kinase activation. Comparison between mice infected by ΔnleC to wildtype C. rodentium demonstrated that loss of NleC did not impact pathogen burdens but did result in more severe colitis. Furthermore, ΔnleC compared to wildtype C. rodentium induced significantly greater chemokine responses. Thus, innate IEC responses are actively suppressed by the host in an attempt to prevent enteric infections. However, once A/E pathogens succeed in infecting their host, they try to suppress IEC responses to prolong the infection. These studies highlight the importance of IEC as the key player in controlling host susceptibility to pathogens and in maintaining a mutualistic relationship with the intestinal commensal microbiota.

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