A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis
A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis
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DOI：
10.1073/pnas.0606412103
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发表时间：
2006-09-26
影响因子：
11.1
通讯作者：
Henriques-Normark, Birgitta
中科院分区：
文献类型：
--
作者：
Muschiol, Sandra;Bailey, Leslie;Henriques-Normark, Birgitta
细胞内病原体沙眼衣原体具有III型分泌（TTS）系统，据信该系统可将一系列效应蛋白传递到包涵膜（inc -蛋白）和宿主细胞质中，从而导致这种常见性病病原体的致病性。最近，小分子被证明可以阻断假结核耶尔森菌的TTS系统。在这里，我们发现其中一种化合物INIP0400在微摩尔浓度下抑制沙眼原体的细胞内复制和感染性，导致小包涵体通常只含有一个或几个网状体（RBs）。在感染时给予高浓度INP0400，可部分阻断初等体进入宿主细胞。早期处理抑制了哺乳动物蛋白14-3-3 ss向包涵体的定位，表明早期诱导的TTS效应物IncG在包涵膜上缺失。在衣原体周期中期用INP0400处理可阻止TTS效应物IncA的分泌和由该蛋白介导的同型囊泡融合。在后期给予INP0400导致RB从包涵膜脱离，同时抑制RB向初级体转化，导致感染性显著降低。
The intracellular pathogen Chlamydia trachomatis possesses a type III secretion (TTS) system believed to deliver a series of effector proteins into the inclusion membrane (Inc-proteins) as well as into the host cytosol with perceived consequences for the pathogenicity of this common venereal pathogen. Recently, small molecules were shown to block the TTS system of Yersinia pseudotuberculosis. Here, we show that one of these compounds, INIP0400, inhibits intracellular replication and infectivity of C trachomatis at micromolar concentrations resulting in small inclusion bodies frequently containing only one or a few reticulate bodies (RBs). INP0400, at high concentration, given at the time of infection, partially blocked entry of elementary bodies into host cells. Early treatment inhibited the localization of the mammalian protein 14-3-3 ss to the inclusions, indicative of absence of the early induced TTS effector IncG from the inclusion membrane. Treatment with INP0400 during chlamydial mid-cycle prevented secretion of the TTS effector IncA and homotypic vesicular fusions mediated by this protein. INP0400 given during the late phase resulted in the detachment of RBs from the inclusion membrane concomitant with an inhibition of RB to elementary body conversion causing a marked decrease in infectivity.