Mechanisms of pathogenesis for Clostridioides difficile toxins 

Seminar Details

Host: Dr. Lanying Zeng

Time: 4:00-5:00 pm

Location: BCBP Rm 108

Seminar Abstract

Clostridioides difficile infection (CDI) is a major cause of healthcare-associated bacterial infections in developed countries. C. difficile toxins such as toxin A (TcdA) and toxin B (TcdB) are key virulence factors responsible for causing the disease associated with CDI. Our overarching goal is to elucidate the molecular and cellular mechanisms underlying TcdB action and pathogenesis. Our previous studies established two independent host receptors for TcdB, including the Wnt receptor Frizzled proteins (FZDs) and chondroitin sulfate proteoglycan 4 (CSPG4). Single cell analysis revealed that neurons and pericytes are two host cell types that express the highest levels of receptors compared with many other cell types in gut tissues, and thus represent the most susceptible cell types to TcdB. We recently showed that TcdB induces secretion of pro-inflammatory neuropeptides from neurons and inflammatory cytokines from pericytes, leading to neurogenic inflammation that damages gut tissues. Here we will investigate at mechanistic levels how TcdB actions on host gut neurons and pericytes contribute to pathogenesis during antibiotic-induced bacterial infection in mouse CDI models in vivo, with a central hypothesis that CDI pathogenesis is initiated by toxin actions on sensory neurons and pericytes. We will further evaluate whether FDA-approved inhibitors against neuropeptide signaling can be beneficial for treatment or prevention across three translationally relevant preclinical models of CDI. These studies will establish a mechanistic understanding of how C. difficile toxins induce host responses that damage tissues and paving the way for developing a host-oriented therapeutic approach for treating CDI.