Regulation of Host Immune Responses by Toll-Interacting Protein During Citrobacter rodentium Infection

Diarrheal diseases are a threat to human health, being the second leading cause of death in children. Diarrheic enterocolitis can be caused by attaching/effacing (A/E) pathogens like enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC). Citrobacter rodentium (CR), a murine A/E pathogen, mimics EPEC and EHEC infections, causing goblet cell depletion, crypt hyperplasia, and leukocyte infiltration into the colonic mucosa. Epithelial cells and innate immune cells detect CR through TLR receptors and increase their production of inflammatory cytokines to limit CR colonization. B cells and CD4+ T cells are activated later in the infection and are critical for pathogen clearance. Toll-interacting protein (Tollip) is an intracellular mediator of several immune mechanisms. Tollip negatively regulates TLR activation, and acts as a mediator of autophagy and endosomal transport. These mechanisms are involved in processes such cytokines expression, antigen presentation and mucus secretion. Although Tollip’s regulation of immune responses is well established, its role in A/E infections remains elusive. This thesis aimed to test the hypothesis that Tollip plays a protective role in CR infection. Using wild-type (WT) and Tollip-deficient (Tollip-/-) mice we demonstrated that lack of Tollip did not affect CR colonization, with both groups exhibiting peak bacterial loads at 8-10 days post-challenge (DPC). While there were no observable differences in colitis levels or apoptotic cells numbers, Tollip-/- mice exhibited excessive pro-inflammatory cytokine expression, including IFNγ, IL-1β and TNFα, likely due to unrestricted TLR activation. No changes in mucus production were observed between groups, but fucose levels in the mucus were lower in the absence of Tollip, probably due to differences in the microbiota. Additionally, Tollip-/- mice exhibited delayed CR clearance, concomitant with increased frequencies of Th17, dendritic cells and neutrophils, and decreased B cell and regulatory T cell populations. These results indicate that adaptive immunity activation may be delayed in the absence of Tollip. This delay may result from impaired endosomal transport, leading to deficient antigen presentation. Moreover, increased cell proliferation in the lamina propria of WT mice after clearance may reflect stromal cell proliferation and tissue repair, which were also delayed in the absence of Tollip. Overall, this thesis demonstrates that Tollip plays a protective role in CR infection by limiting the overexpression of pro-inflammatory cytokines and promoting bacterial clearance.

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