Consequences of vaginal microbiota on IFNγ-mediated clearance of Chlamydia trachomatis

阴道微生物群对 IFNγ 介导的沙眼衣原体清除的影响

• 批准号: 9540785
• 负责人: Ashok A Aiyar
• 金额: $ 60.06万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-08 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9540785
• 关键词: Address; Affect; African American; Anabolism; Anaerobic Bacteria; Animals; Bacteria; Bacterial Vaginosis; Biological Factors; Biological Models; Cell model; Cells; Cervical; Chlamydia Infections; Chlamydia trachomatis; Chronic; Classification; Clinic; Clinical; Clinical Data; Coculture Techniques; DNA; Data; Ectopic Pregnancy; Endocervix; Enrollment; Environment; Enzymes; Epithelial Cells; Essential Amino Acids; Failure; Gene Expression; Gene Expression Profile; Generations; Genes; Genital system; Genitourinary system; Growth; Health; Human; Immune response; Immunity; Immunologics; In Vitro; Indoles; Infection; Infertility; Interferon Type II; Interferons; Intervention; Knowledge; Light; Longitudinal Studies; Mediating; Methods; Modeling; Molecular; Natural History; Neonatal; Outcome; Pathway interactions; Patients; Pelvic Inflammatory Disease; Pharmacology; Physiological; Population; Prevalence; Prevotella; Public Health; Publishing; RNA; Recombinant DNA; Reporting; Reproductive Health; Resolution; Role; Sampling; Sexually Transmitted Diseases; Site; Testing; Therapeutic; Tryptophan; Tryptophan 2,3 Dioxygenase; Tryptophan Synthase; Tryptophanase; Tube; Vaccines; Vagina; Visit; Woman; clinical effect; co-infection; cohort; cytokine; design; female fertility; high risk; immune clearance; improved; in vitro Model; in vivo; inhibitor/antagonist; member; microbiome; microbiome analysis; microbiome components; microbiota; novel; prevent; protective effect; reproductive; sexually active; small molecule; small molecule inhibitor; translational study; vaginal microbiome; vaginal microbiota; welfare

Chlamydia trachomatis (CT) infections are a major public health concern as they can adversely affect female fertility and neonatal health. While natural history studies indicate that some women spontaneously clear their infection, the physiological conditions that permit spontaneous clearance of CT remain elusive. Understand the latter is key to developing an effective vaccine that to prevent CT infection and its devastating consequences. In vitro and in vivo studies indicate that interferon gamma (IFNγ) is the primary protective cytokine against CT. IFNγ induces the host enzyme indoleamine 2,3-dioxygenase (IDO1) that degrades tryptophan, an essential amino acid for CT, which cannot synthesize tryptophan de novo. All clinical genital CT isolates have evolved a mechanism to evade the effect of IFNγ, specifically they can express a functional tryptophan synthase that salvages exogenously provided indole to generate tryptophan within the intracellular chlamydial inclusion where it is impervious to IDO1. While neither CT, nor human cells, synthesize indole, some members of the vaginal microbiome that increase greatly in number and proportion during bacterial vaginosis (BV), can do so. Thus, we hypothesize that the composition of the vaginal microbiome, and its capacity to provide indole, modulates the efficacy of IFNγ-dependent host immunity against CT. This hypothesis is supported by our existing clinical data; although all women who spontaneously cleared CT infection had high endocervical IFNγ levels, so did ~40% of women who failed to clear infection. We propose to rigorously test this hypothesis using a cohort of high-risk African-American women attending our STD clinic in New Orleans. The cohort will be stratified into groups that spontaneously clear CT infections (~28% in our cohort) or fail to clear CT infection between enrollment and return-for-treatment visits. By focusing on women who spontaneously clear infection, and the ~40% of non- clearing women who meet the threshold endocervical IFNγ levels observed in clearers, we will investigate the following objectives: 1) Determine the infection micromilieu (tryptophan/indole/IFNγ/CT load & gene expression profile) correlates of clearance; 2) Determine differences in the prevalent vaginal microbiome, and its indole- generation capacity, between clearers and non-clearers; and 3) Using a novel endocervical epithelial cell model, directly test the capacity of indole-producing microbiome members to limit IFNγ-mediated CT clearance, and evaluate the efficacy of known small molecule indole biosynthesis inhibitors to augment IFNγ-mediated CT clearance during co-infections. The outcomes from the proposed studies will provide essential information needed to design novel immunological and pharmacological approaches that improve clinical outcomes for CT- infected patients. Modeling the mechanisms used during spontaneous clearance will define the effects of co- infection on the efficacy of the host response to CT-infection. This will significantly improve patient health and welfare in light of the tremendous human and financial toll that is imposed by genital CT infections.

衣原体沙眼（CT）感染是一个主要的公共卫生问题，因为它们可能会对 女性生育能力和新生儿健康。虽然自然历史研究表明有些女性赞助 他们的感染，允许赞助商自发清除CT的身体状况仍然难以捉摸。理解 后者是开发有效疫苗的关键，该疫苗可防止CT感染及其毁灭性后果。 体外和体内研究表明，干扰素γ（IFNγ）是针对CT的主要受保护的细胞因子。 IFNγ诱导宿主酶吲哚胺2,3-二氧酶（IDO1）降解色氨酸，这是必不可少的 CT的氨基酸，该氨基酸无法合成从头开始的色氨酸。所有临床生殖器CT分离株均进化 逃避IFNγ作用的机制，具体来说，它们可以表达功能性色氨酸合酶 外源提供吲 IDO1不可渗。虽然CT和人类细胞都不合成吲哚，但某些阴道成员 在细菌阴道化（BV）期间数量和比例增加的微生物组可以做到这一点。所以，我们 假设阴道微生物组的组成及其提供吲哚的能力，可调节 IFNγ依赖性宿主免疫学对CT的功效。我们现有的临床数据支持了这一假设。 尽管所有赞助清除CT感染的女性均具有高元元IFNγ水平，但约有40％ 未能清除感染的妇女。我们建议使用一系列高风险来严格检验该假设 非裔美国妇女在新奥尔良的性病诊所就读。该队列将分为 赞助清除CT感染（我们的队列中约28％）或在入学和 返回治疗访问。通过专注于赞助的清除感染的妇女以及约40％的非 - 清除符合范围内观察到的阈值IFNγ水平的妇女，我们将调查 以下对象：1）确定感染Micromilieu（色氨酸/吲哚/IFNγ/CT负载和基因表达 轮廓）清除相关； 2）确定流行的阴道微生物组及其吲哚 - 发电能力，清除者和非清算者之间； 3）使用新型宫颈上皮细胞模型， 直接测试产生吲哚的微生物组成员以限制IFNγ介导的CT间隙的能力，并且 评估已知的小分子吲哚生物合成抑制剂的效率增强IFNγ介导的CT 共同感染期间的清理率。拟议研究的结果将提供基本信息 需要设计新型免疫学和药物方法，以改善CT-的临床结果 感染的患者。对自发清除期间使用的机制进行建模将定义共同的影响 关于宿主对CT感染效率的感染。这将大大改善患者健康和 鉴于生殖器CT感染造成的巨大人类和经济损失。