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， 生殖健康和新生儿存活率。干扰素γ（IFNg）被提议用于保护免受CT感染 通过诱导色氨酸分解代谢酶吲哚胺2，3-双加氧酶1（IDO 1）。随之而来的消耗 的色氨酸使CT缺乏这种必需氨基酸，导致细菌根除。通过表达 衣原体酶色氨酸合成酶（TS），生殖器血清型CT可以逃避IFNg的影响，如果 微生物代谢物吲哚存在于感染微环境中。TS可以在细胞内挽救吲哚， 衣原体包涵体以产生色氨酸。TS的表达受色氨酸操纵子的严格调控 阻遏物（TrpR），其仅在色氨酸不存在时允许操纵子的转录。我们最近 发现由肠道微生物组产生的吲哚衍生物，称为TrpR去阻遏物， 衣原体TS的表达。此外，当TS在不存在吲哚的情况下表达时，该酶快速地表达。 使丝氨酸脱氨基以产生氨（NH3），一种已知的杀菌化合物。在评估影响时， 在不同衣原体血清型上的TrpR去阻遏物，我们发现，尽管去阻遏物同样 在它们之间，NH3的生产变化很大。使用各种方法的组合，在这里，我们 建议：1）确定CT吸收TS产生的NH3的方法; 2）确定 血清型之间TS的序列差异决定了它们维斯氨的催化特性 一代我们的研究结果将允许设计新的药理学方法， 通过增强保护性宿主反应的效果来抑制衣原体感染。