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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

基本信息

批准号：
10198719
负责人：
Ashok A Aiyar
金额：
$ 18.38万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-19 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198719
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 Genitalia 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

项目摘要

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）感染是可产生不利影响的主要公共卫生问题