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.
|Wang, Yuanguo; Wang, Shaohui; Bouillaut, Laurent et al. (2018) Oral Immunization with Nontoxigenic Clostridium difficile Strains Expressing Chimeric Fragments of TcdA and TcdB Elicits Protective Immunity against C. difficile Infection in Both Mice and Hamsters. Infect Immun 86:|
|Li, Chunhui; Teng, Peng; Peng, Zhong et al. (2018) Bis-Cyclic Guanidines as a Novel Class of Compounds Potent against Clostridium difficile. ChemMedChem 13:1414-1420|
|Zhu, Duolong; Sorg, Joseph A; Sun, Xingmin (2018) Clostridioides difficile Biology: Sporulation, Germination, and Corresponding Therapies for C. difficile Infection. Front Cell Infect Microbiol 8:29|
|Teng, Peng; Li, Chunhui; Peng, Zhong et al. (2018) Facilely accessible quinoline derivatives as potent antibacterial agents. Bioorg Med Chem 26:3573-3579|
|Wang, Yuanguo; Wang, Shaohui; Kelly, Ciaran P et al. (2018) TPL2 Is a Key Regulator of Intestinal Inflammation in Clostridium difficile Infection. Infect Immun 86:|
|Peng, Zhong; Addisu, Anteneh; Alrabaa, Sally et al. (2017) Antibiotic Resistance and Toxin Production of Clostridium difficile Isolates from the Hospitalized Patients in a Large Hospital in Florida. Front Microbiol 8:2584|