EPITHELIAL-LYMPHOID CROSSTALK VIA IL-1, DEFENSE AGAINST CITROBACTER RODENTIUM

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The objective of this proposal is to determine the role of IL-1 receptor type I (IL-1R1) in host defense against Citrobacter rodentium infection. We hypothesize that IL-1R1-initiated signaling is essential for MyD88-dependent mucosal immunity against Citrobacter rodentium. Specific Aim One: Determine the role of IL-1R1 signaling in intestinal epithelial cell homeostasis in C. rodentium infection. We hypothesize that IL-1R signaling is essential for intestinal epithelial cell proliferation, functional integrity, and antimicrobial peptide/protein expression in C. rodentium infection. Using HT-29 and Mode-K cells, we will determine the effects of IL-1¿ on cell proliferation, migration, and adhesion, as well as the expression of antimicrobial peptides and proteins, proinflammatory cytokine, and molecules involved in gap junction and tight junction. In addition, we will compared the clinical signs, colonic hyperplasia, and intestinal mucosal integrity in WT, MyD88 KO, IL-1R1 KO, and IL-18 KO mice infected with C. rodentium. Specific Aim Two: Determine the role of IL-1R signaling in mucosal innate immunity in C. rodentium infection. We hypothesize that IL-1R signaling is required for the induction and recruitment of neutrophils and the production of inflammatory cytokines by epithelial and immune cells in C. rodentium infection. We will evaluate the colonic production of proinflammatory cytokines, intestinal infiltration of neutrophils and macrophages, epithelial antimicrobial peptides and proteins, bacterial burden in segments of colon, liver, and spleen, and intestinal immunoglobulin levels on WT, MyD88 KO, IL-1R1 KO, and IL-18 KO mice infected with C. rodentium.