C. difficile infection (CDI) is the most common cause of infectious diarrhea in healthcare settings with about 453.000 cases and 29,000 deaths yearly in US per CDC report in 2015. A continual rise in severe CDI has been observed worldwide due to the emergence of hypervirulent strains. CDI symptoms range from diarrhea to intestinal inflammation/lesion and death. Symptoms are mainly caused by two exotoxins TcdA and TcdB, which glucosylate Rho GTPases, including RhoA, Rac1 and CDC42 within cells, leading to disruption of cytoskeleton and tight junctions. Both toxins share similar domain structures, including the N-terminal glucosyltransferase domain (GT), the autocatalytic cysteine proteinase domain (CPD), the translocation domain (TMD), and the C-terminal receptor binding domain (RBD). Only the GT is released into cytosol after auto-cleavage of the toxin by its CPD. The course of CDI is characterized by an initial intestinal inflammatory process followed by a systemic inflammatory response. However, the mechanism by which TcdA/TcdB induce a potent inflammatory response, the hallmark of the disease, is unclear. Our long-term goal is to understand the mechanisms mediating intestinal inflammation by C. difficile toxins and to utilize this knowledge for designing better interventions to reduce the incidence and severity of CDI. The objective of this study is to elucidate the role of TPL2 in the pathogenesis of CDI. We hypothesize that TPL2 ablation will down regulate TcdA/TcdB-induced activation of MAPK, leading to reduced TNF-? / IL-6 production, thus reducing toxin-caused intestinal inflammation, tissue injury and mortality. To test our hypothesis, two specific aims will be pursued.
In aim 1, we will evaluate the role of TPL2 in the pathogenesis of CDI using mouse models.
In aim 2, we will investigate the role of TPL2 in the signaling pathway mediating TcdA/TcdB-induced production of TNF-? and IL-6 by bone marrow-derived macrophages.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
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Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
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Saslowsky, David E
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University of South Florida
Schools of Medicine
United States
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