Severe tryptophan starvation blocks onset of conventional persistence and reduces reactivation of Chlamydia trachomatis
Severe tryptophan starvation blocks onset of conventional persistence and reduces reactivation of Chlamydia trachomatis
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DOI：
10.1128/iai.00668-07
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发表时间：
2007-11-01
影响因子：
3.1
通讯作者：
Cresswell, Peter
中科院分区：
文献类型：
--
作者：
Leonhardt, Ralf M.;Lee, Seung-Joon;Cresswell, Peter
沙眼衣原体的细胞内生存依赖于内化后不久微生物的蛋白质合成。抑制细菌翻译的药物抑制了寄生虫空泡(包涵体)早期向微管组织中心(MTOC)的运输，并促进了它与通常被衣原体阻止的溶酶体的融合。干扰素诱导的吲哚-2，3-双加氧酶(IDO)耗尽细胞色氨酸库被认为是控制沙眼衣原体感染的主要先天免疫机制，细菌可以通过转变为不可复制但高度可重新激活的持续状态来做出反应。然而，IDO介导的严重色氨酸饥饿是否足以完全阻止衣原体的生命周期，从而抵消持久性的开始，目前尚不清楚。在这里，我们证明了在外源性色氨酸浓度较低的情况下，相当一部分沙眼衣原体细菌无法通过MTOC或在伽马干扰素诱导的人类细胞中切换到传统的持续状态。这些生物体分散在细胞外围，不保留感染性，只表现出低转录活性。重要的是，这些异常衣原体细菌在细胞色氨酸库补充后重新激活的速度要低得多。因此，具有高IDO活性的细胞中严重的色氨酸耗竭对衣原体发育的影响比先前描述的更严格。
The intracellular survival of the bacterial pathogen Chlamydia trachomatis depends on protein synthesis by the microbe soon after internalization. Pharmacologic inhibition of bacterial translation inhibits early trafficking of the parasitophorous vacuole (inclusion) to the microtubule-organizing center (MTOC) and promotes its fusion with lysosomes, which is normally blocked by Chlamydia. Depletion of cellular tryptophan pools by gamma interferon-inducible indoleamine-2,3-dioxygenase (IDO) is believed to be the major innate immune mechanism controlling C. trachomatis infection in human cells, an action to which the bacteria can respond by converting into a nonreplicating but highly reactivatable persistent state. However, whether severe IDO-mediated tryptophan starvation can be sufficient to fully arrest the chlamydial life cycle and thereby counteract the onset of persistence is unknown. Here we demonstrate that at low exogenous tryptophan concentrations a substantial fraction of C. trachomatis bacteria fail to traffic to the MTOC or to switch into the conventional persistent state in gamma interferon-induced human cells. The organisms stay scattered in the cell periphery, do not retain infectivity, and display only low transcriptional activity. Importantly, the rate at which these aberrant Chlamydia bacteria become reactivated upon replenishment of cellular tryptophan pools is substantially lower. Thus, severe tryptophan depletion in cells with high IDO activity affects chlamydial development more rigorously than previously described.