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

调节衣原体色氨酸合酶产生氨有害作用的因素

• 批准号: 10040215
• 负责人: Ashok A Aiyar
• 金额: $ 22.05万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-19 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040215
• 关键词: Affect; Ammonia; Anabolism; Antibiotic Prophylaxis; Assimilations; Automobile Driving; Azithromycin; Bacteria; Biochemical; Biological; Chlamydia Infections; Chlamydia trachomatis; Clinical; Columnar Epithelium; Data; Deamination; Development; Ectopic Pregnancy; Enzymes; Epithelial Cells; Equilibrium; Essential Amino Acids; Generations; Genetic Transcription; Genital system; Genome; Glutamine; Human; Immune response; Immunity; Incentives; Indoles; Infection; Interferon Type II; Intervention; Left; Ligase; Lipids; Mammalian Oviducts; Methods; Minor; Mutation; Natural Immunity; Operon; Outcome; Outcome Study; Pelvic Inflammatory Disease; Pharmacology; Process; Production; Property; Public Health; Publications; Publishing; Pyruvate; Reaction; Regimen; Reporting; Repression; Reproductive Health; Research; Resistance; Serine; Sexually Transmitted Diseases; Starvation; Tryptophan; Tryptophan 2,3 Dioxygenase; Tryptophan Synthase; Variant; Woman; bactericide; cytokine; design; genital microbiome; gut microbiome; immune clearance; microbial; microbiome; molecular targeted therapies; neonate; novel; novel therapeutics; pathogen; protective effect; tubal infertility; urogenital tract

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.

生殖器沙眼衣原体！ (CT) 感染是一个主要的公共卫生问题，可能会产生不利影响 生殖健康和新生儿存活。干扰素 γ (IFNg) 被提议用于预防 CT 感染 通过诱导色氨酸分解酶吲哚胺 2,3-双加氧酶 1 (IDO1)。随之而来的枯竭 色氨酸使 CT 缺乏这种必需氨基酸，从而导致细菌根除。通过表达 衣原体酶色氨酸合酶 (TS)、CT 生殖血清型可以逃避 IFNg 的影响，如果 感染微环境中存在微生物代谢产物吲哚。 TS 可以在 衣原体包涵体产生色氨酸。 TS 表达受到色氨酸操纵子的严格调控 阻遏蛋白（TrpR），仅当色氨酸不存在时才允许操纵子转录。我们最近 发现肠道微生物组产生的吲哚衍生物（称为 TrpR 去阻遏物）可迅速诱导 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。在评估效果的同时 TrpR 去阻遏物对不同的衣原体血清型，我们发现尽管去阻遏物的效果是相同的 它们之间的效率不同，NH3 的产量差异很大。在这里我们使用多种方法的组合 建议： 1) 确定 CT 吸收 TS 产生的 NH3 的方法； 2) 确定是否 血清型之间 TS 的序列差异决定了它们相对于氨的催化特性 一代。我们的研究结果将允许设计新的药理学方法来对抗 通过增强宿主保护反应的效果来抑制衣原体感染。