艰难拟梭菌毒素致病机制及毒素基因调控的研究进展

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

艰难拟梭菌(Clostridioides difficile)是一种产芽孢的革兰氏阳性专性厌氧杆菌,是引起抗生素相关性腹泻的主要致病菌。艰难拟梭菌产生的毒素A和毒素B在其致病过程中发挥关键作用。毒素发挥毒性作用依赖其4个功能结构域:葡萄糖基转移酶结合域、半胱氨酸蛋白酶结合域、易位域和受体结合域。毒素的受体结合域识别并结合细胞表面受体,介导毒素内吞并形成内体。经过自体催化切割,毒素将真正的毒性片段——葡萄糖基转移酶结合域释放到胞浆中,葡萄糖基转移酶能够失活宿主肠上皮细胞内的GTP酶导致细胞骨架解聚和坏死,进而引起腹泻和伪膜性结肠炎等临床症状。艰难拟梭菌毒素产生受致病基因座内及基因座外许多调控因子的调节。tcdR和tcdC基因位于致病基因座内,对毒素基因的表达分别起促进和抑制作用,而基因座外如spo0A、codY等基因则通过抑制tcdR的表达从而间接影响毒素蛋白产生。本文将重点介绍艰难拟梭菌毒素的致病过程和影响毒素基因表达的分子调控机制,以期为开发针对毒素的治疗手段提供新思路。

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.