Factors that modulate the deleterious effect of ammonia generation by chlamydial tryptophan synthase

生殖器沙眼衣原体！(CT)感染是一个主要的公共卫生问题，可能会对 生殖健康和新生儿存活率。建议使用干扰素-γ(IFNG)来预防CT感染 通过诱导色氨酸分解酶吲哚-2，3-双加氧酶1(IDO1)。随之而来的枯竭 色氨酸使CT缺乏这种必需的氨基酸，从而导致细菌根除。通过表达 沙眼衣原体色氨酸合成酶(TS)、生殖器血清型可逃脱IFNG的影响 微生物代谢产物吲哚存在于感染微环境中。TS可以挽救吲哚 衣原体包涵体产生色氨酸。TS的表达受到色氨酸操纵子的严格调控 抑制子(Trpr)，只有在没有色氨酸的情况下才允许操纵子转录。我们最近 发现由肠道微生物群产生的吲哚衍生物，被称为Trpr去抑制物，迅速诱导 衣原体TS的表达。此外，当TS在没有吲哚的情况下表达时，该酶迅速 使丝氨酸脱氨生成氨(NH3)，这是一种已知的杀菌化合物。在评估其效果时 在不同的衣原体血清型上，我们发现尽管去抑制作用是相同的 它们之间的效率很高，NH3的产量差别很大。在这里，我们结合使用多种方法 建议：1)确定CT同化TS产生的NH3的方法；2)确定 不同血清型TS的序列差异决定了它们对氨的催化性能 一代。我们的发现结果将允许设计新的药理方法来对抗 衣原体感染通过增强保护性宿主反应的效果。

Genital Chlamydia trachomatis! (CT) infections are a major public health concern that can adversely affect reproductive health and neonate survival. Interferon gamma (IFNg) is proposed to protect against CT infection by inducing the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1). The ensuing depletion of tryptophan starves CT of this essential amino-acid leading to bacterial eradication. By expressing the chlamydial enzyme tryptophan synthase (TS), genital serovars of CT can escape the effects of IFNg if the microbial metabolite indole is present in the infection microenvironment. TS can salvage indole within the chlamydial inclusion to generate tryptophan. TS expression is tightly regulated by the tryptophan operon repressor (TrpR), which permits transcription of the operon only when tryptophan is absent. We recently discovered that indole derivatives produced by the gut microbiome, termed TrpR de-repressors, rapidly induce the expression of chlamydial TS. Further, when TS is expressed in the absence of indole, the enzyme rapidly deaminates serine to generate ammonia (NH3), a known bactericidal compound. While evaluating the effect of TrpR de-repressors on different chlamydial serovars, we discovered that although de-repression was equally efficient between them, the production of NH3 varied dramatically. Using a combination of approaches, here we propose to: 1) Identify methods by which CT can assimilate NH3 produced by TS; and 2) Determine whether sequence differences in TS between serovars determines their catalytic properties vis-à-vis ammonia generation. The outcome of our findings will permit the design of novel pharmacological approaches against chlamydial infection by augmenting the effect of protective host responses.