Citrobacter rodentium translocated intimin receptor (Tir) is an essential virulence factor needed for actin condensation, intestinal colonization and colonic hyperplasia in mice
Citrobacter rodentium translocated intimin receptor (Tir) is an essential virulence factor needed for actin condensation, intestinal colonization and colonic hyperplasia in mice
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DOI：
10.1046/j.1365-2958.2003.03429.x
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发表时间：
2003-04-01
影响因子：
3.6
通讯作者：
Finlay, BB
中科院分区：
文献类型：
--
作者：
Deng, WY;Vallance, BA;Finlay, BB
以小鼠轮状柠檬酸杆菌感染为相关的小动物模型，研究人的肠出血性大肠埃希菌(EHEC)和致病性肠出血性大肠杆菌(EPEC)感染。肠源性大肠埃希菌和肠出血性大肠杆菌将TIR转运到宿主细胞膜，在宿主细胞膜上作为细菌粘附素内膜的受体，在粘附性细菌下的肌动蛋白凝聚过程中发挥核心作用。在这份报告中，我们研究了轮状冠菌TIR在体外和体内的功能。与EPEC类似，轮状梭菌TIR是酪氨酸磷酸化的，是肌动蛋白缩合所必需的。柠檬酸杆菌TIR和EPEC TIR在功能上是可互换的，都需要酪氨酸磷酸化来介导肌动蛋白重排。相反，柠檬酸TIR支持EHEC中不依赖于酪氨酸磷酸化的肌动蛋白成核，而EHEC TIR不能取代柠檬酸TIR来实现这一功能。这表明轮状杆菌和EPEC使用了不同于EHEC的肌动蛋白成核机制。我们还发现，在感染过程中，轮状芽胞杆菌在体内表达TIR并将其转移到小鼠的肠道细胞中。这是第一次直接证明III型效应器在体内被任何病原体转移到自然宿主中。此外，我们还发现TIR，而不是它的酪氨酸磷酸化，对于轮齿芽胞杆菌在小鼠大肠的定植和诱导附着/消失(A/E)病变和结肠增生是必不可少的，并且EPEC TIR和EHEC TIR在体内都可以替代柠檬酸杆菌TIR来发挥这些活性。这些结果表明，TIR在该感染模型中是一个重要的毒力因子。这些数据还表明，TIR酪氨酸磷酸化的功能及其随后的肌动蛋白成核活性对于小鼠肠道中轮状芽胞杆菌的定植和诱导A/E病变和结肠增生，从而使这种A/E病原体的定植和疾病与肌动蛋白凝聚分离是不必要的。
Citrobacter rodentium infection of mice serves as a relevant small animal model to study enterohaemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) infections in man. Enteropathogenic E. coli and EHEC translocate Tir into the host cytoplasmic membrane, where it serves as the receptor for the bacterial adhesin intimin and plays a central role in actin condensation beneath the adherent bacterium. In this report, we examined the function of C. rodentium Tir both in vitro and in vivo . Similar to EPEC, C. rodentium Tir is tyrosine phosphorylated and is essential for actin condensation. Citrobacter Tir and EPEC Tir are functionally interchangeable and both require tyrosine phosphorylation to mediate actin rearrangements. In contrast, Citrobacter Tir supports actin nucleation in EHEC independent of tyrosine phosphorylation, while EHEC Tir cannot replace Citrobacter Tir for this function. This indicates that C. rodentium and EPEC use an actin nucleating mechanism different from EHEC. We also found that Tir is expressed and translocated into mouse enterocytes in vivo by C. rodentium during infections. This represents the first direct demonstration of a type III effector translocated in vivo into a natural host by any pathogen. In addition, we showed that Tir, but not its tyrosine phosphorylation, is essential for C. rodentium to colonize the large bowel and induce attaching/effacing (A/E) lesions and colonic hyperplasia in mice, and that both EPEC Tir and EHEC Tir can substitute for Citrobacter Tir for these activities in vivo . These results thus demonstrate that Tir is an essential virulence factor in this infection model. The data also show that the function of Tir tyrosine phosphorylation and its subsequent actin nucleating activity are not essential for C. rodentium colonization of the mouse gut nor for inducing A/E lesions and colonic hyperplasia, thereby uncoupling colonization and disease from actin condensation for this A/E pathogen.