Bacterial Genotoxin Accelerates Transient Infection-Driven Murine Colon Tumorigenesis.
Bacterial Genotoxin Accelerates Transient Infection-Driven Murine Colon Tumorigenesis.
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DOI：
10.1158/2159-8290.cd-21-0912
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发表时间：
2022-01
期刊：
影响因子：
28.2
通讯作者：
Wan F
中科院分区：
文献类型：
--
作者：
Liu Y;Fu K;Wier EM;Lei Y;Hodgson A;Xu D;Xia X;Zheng D;Ding H;Sears CL;Yang J;Wan F
与持续性细菌感染相关的慢性和低度炎症与结肠肿瘤的发展有关;然而，细菌驱动的结肠肿瘤发生中短暂和自限性感染的影响仍然是个谜。UshA是一种新型的A/E基因毒素，主要作用于人类致病性大肠杆菌、肠出血性大肠杆菌等。大肠杆菌（EHEC）和它们的鼠等效物啮齿柠檬酸杆菌（CR）。UshA具有直接的DNA消化活性，具有催化组氨酸-天冬氨酸二联体。通过III型分泌系统（T3 SS）注射到宿主细胞中，UshA在体外和体内感染期间触发DNA损伤并引发致瘤转化。此外，UshA在遗传易感的ApcMinΔ716/+小鼠中CR感染加速的结肠肿瘤发生中起着不可或缺的作用。总的来说，我们的研究结果表明，UshA，作为一种细菌T3 SS依赖性基因毒素，在促进短暂的和非侵入性的细菌感染加速小鼠结肠肿瘤发生中起着关键作用。
Chronic and low-grade inflammation associated with persistent bacterial infections has been linked to colon tumor development; however, the impact of transient and self-limited infections in bacterially-driven colon tumorigenesis has remained enigmatic. Here we report that UshA is a novel genotoxin in attaching/effacing (A/E) pathogens, which includes the human pathogens enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC), and their murine equivalent Citrobacter rodentium (CR). UshA harbors direct DNA digestion activity with a catalytic histidine-aspartic acid dyad. Injected via the Type III Secretion System (T3SS) into host cells, UshA triggers DNA damage and initiates tumorigenic transformation during infections in vitro and in vivo. Moreover, UshA plays an indispensable role in CR infection-accelerated colon tumorigenesis in genetically susceptible ApcMinΔ716/+ mice. Collectively, our results reveal that UshA, functioning as a bacterial T3SS-dependant genotoxin, plays a critical role in prompting transient and noninvasive bacterial infection-accelerated colon tumorigenesis in mice.