Advances in pathogenesis of Clostridioides difficile and regulation of toxin gene expression

Abstract:

Clostridioides difficile, a spore-forming Gram-positive obligate anaerobic bacterium, is the main pathogen causing antibiotic-associated diarrhea. Two toxins produced by C. difficile, toxin A and toxin B, play a key role in its pathogenesis. The roles of toxins depend on four functional domains: glucosyltransferase domain, cysteine protease domain, transmembrane domain, and receptor-binding domain. The receptor-binding domain recognizes and binds to the receptors on cell surface, mediating toxin endocytosis to form endosomes. After autocatalytic cleavage, the toxic fragment, glucosyltransferase domain, is released into the cytoplasm. Glucosyltransferase can inactivate GTPase in host intestinal epithelial cells, leading to cytoskeletal depolymerization and necrosis, which causes clinical symptoms such as diarrhea and pseudomembranous colitis. The production of toxins is regulated by a variety of factors within and outside the pathogenicity locus. Located in the pathogenicity locus, tcdR promotes and tcdC inhibits the expression of the toxin genes, respectively. The genes outside the locus, such as spo0A and codY, indirectly affect the production of toxins by inhibiting the expression of tcdR. This review focuses on the pathogenic process of toxins and the molecular mechanism of the regulation of toxin gene expression, hoping to provide new ideas for the development of toxin-targeted therapies.