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Abstract：
Clostridioides difficile, a Gram-positive anaerobic bacterium, is the leading cause of hospital-acquired antibiotic-associated diarrhea worldwide. The severity of C. difficile infection (CDI) varies, ranging from mild diarrhea to life-threatening conditions such as pseudomembranous colitis and toxic megacolon. Central to the pathogenesis of the infection are toxins produced by C. difficile, with toxin A (TcdA) and toxin B (TcdB) as the main virulence factors. Additionally, some strains produce a third toxin known as C. difficile transferase (CDT). Toxins damage the colonic epithelium, initiating a cascade of cellular events that lead to inflammation, fluid secretion, and further tissue damage within the colon. Mechanistically, the toxins bind to cell surface receptors, internalize, and then inactivate GTPase proteins, disrupting the organization of the cytoskeleton and affecting various Rho-dependent cellular processes. This results in a loss of epithelial barrier functions and the induction of cell death. The third toxin, CDT, however, functions as a binary actin-ADP-ribosylating toxin, causing actin depolymerization and inducing the formation of microtubule-based protrusions. In this review, we summarize our current understanding of the interaction between C. difficile toxins and host cells, elucidating the functional consequences of their actions. Furthermore, we will outline how this knowledge forms the basis for developing innovative, toxin-based strategies for treating and preventing CDI.
摘要：
艰难梭菌，革兰氏阳性厌氧菌,是全球医院获得性抗生素相关性腹泻的主要原因。艰难梭菌感染（CDI）的严重程度各不相同，从轻度腹泻到危及生命的疾病，如伪膜性结肠炎和中毒性巨结肠。感染发病机制的核心是艰难梭菌产生的毒素，以毒素A(TcdA)和毒素B(TcdB)为主要毒力因子。此外,一些菌株产生称为艰难梭菌转移酶(CDT)的第三种毒素。毒素损伤结肠上皮,引发一系列导致炎症的细胞事件，液体分泌,以及结肠内的进一步组织损伤。机械上,毒素与细胞表面受体结合，内化，然后灭活GTPase蛋白，破坏细胞骨架的组织并影响各种Rho依赖性细胞过程。这导致上皮屏障功能的丧失和细胞死亡的诱导。第三种毒素,CDT,然而,作为二元肌动蛋白-ADP-核糖基化毒素，引起肌动蛋白解聚并诱导微管基突起的形成。在这次审查中,我们总结了我们目前对艰难梭菌毒素和宿主细胞之间相互作用的理解，阐明他们行为的功能后果。此外，我们将概述这些知识如何构成发展创新的基础，用于治疗和预防CDI的基于毒素的策略。
