Treatment of Chlamydia trachomatis with a small molecule inhibitor of the Yersinia type III secretion system disrupts progression of the chlamydial developmental cycle
Treatment of Chlamydia trachomatis with a small molecule inhibitor of the Yersinia type III secretion system disrupts progression of the chlamydial developmental cycle
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DOI：
10.1111/j.1365-2958.2006.05347.x
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发表时间：
2006-09-01
影响因子：
3.6
通讯作者：
Fields, K. A.
中科院分区：
文献类型：
--
作者：
Wolf, K.;Betts, H. J.;Fields, K. A.
专性细胞内沙眼衣原体具有两个阶段的发育周期，表现为具有感染性的代谢惰性基本体(EBS)向更大的代谢活性网状小体(RBS)的分化。这个循环是通过将RB分裂回一群休眠的EBS的异步分化来完成的，这些EBS在宿主细胞裂解后可以发起更多轮的感染。衣原体表达一种III型分泌系统(T3SS)，它可能通过分泌抗宿主蛋白来建立和维持细胞内允许的生态位。我们推测T3SS活性对衣原体的发育和发病是必不可少的。然而，缺乏基因系统使确立T3SS任何作用的努力变得混乱。因此，我们使用了小分子耶尔森氏菌T3SS抑制剂N‘-(3，5-dibromo-2-hydroxybenzylidene)-4-nitrobenzohydrazide，，命名为化合物1(C1)，以检查衣原体T3SS与发育的相互依赖。C1处理抑制沙眼衣原体的发育，但不抑制表达T4SS的伯氏柯克斯体的发育，且呈剂量依赖关系。尽管衣原体仍然存活并具有代谢活性，但它们不能显著分裂，Rb向EB的分化受到抑制。这些效应发生在没有宿主细胞细胞毒性的情况下，并且可以通过清除C1而可逆。我们进一步证明，在经C1处理的衣原体培养物中，T3S底物的分泌受到干扰。因此，我们提供了C1可以抑制沙眼衣原体发育和T3SS活性的证据，并提出了一个模型，在该模型中，沙眼衣原体发育周期的进展需要一个完全功能的T3SS。
The obligate intracellular bacterium Chlamydia trachomatis possesses a biphasic developmental cycle that is manifested by differentiation of infectious, metabolically inert elementary bodies (EBs) to larger, metabolically active reticulate bodies (RBs). The cycle is completed by asynchronous differentiation of dividing RBs back to a population of dormant EBs that can initiate further rounds of infection upon lysis of the host cell. Chlamydiae express a type III secretion system (T3SS) that is presumably employed to establish and maintain the permissive intracellular niche by secretion of anti-host proteins. We hypothesize that T3SS activity is essential for chlamydial development and pathogenesis. However, the lack of a genetic system has confounded efforts to establish any role of the T3SS. We therefore employed the small molecule Yersinia T3SS inhibitor N'-(3,5-dibromo-2-hydroxybenzylidene)-4-nitrobenzohydrazide, designated compound 1 (C1), to examine the interdependence of the chlamydial T3SS and development. C1 treatment inhibited C. trachomatis but not T4SS-expressing Coxiella burnetii development in a dose-dependent manner. Although chlamydiae remained viable and metabolically active, they failed to divide significantly and RB to EB differentiation was inhibited. These effects occurred in the absence of host cell cytotoxicity and were reversible by washing out C1. We further demonstrate that secretion of T3S substrates is perturbed in C1-treated chlamydial cultures. We have therefore provided evidence that C1 can inhibit C. trachomatis development and T3SS activity and present a model in which progression of the C. trachomatis developmental cycle requires a fully functional T3SS.