Role of Interferon-gamma in Clearance of Chlamydia trachomatis Infection in Women

项目摘要 博士乔丹是印第安纳州大学医学院的终身助理教授， 是一个独立的医生科学家研究人类免疫机制的保护， 沙眼衣原体（Ct）感染是世界范围内最普遍的细菌性性传播感染， 生殖道疾病的主要原因。控制措施未能遏制Ct感染率的上升， Ct疫苗开发受到赋予Ct免疫力的人类免疫应答中的知识缺口的阻碍。 在动物模型中，由T细胞和可能的自然杀伤（NK）细胞产生的干扰素-γ（IFN-γ）是 衣原体清除所需，可能通过消耗细胞内色氨酸; Ct的必需氨基酸 生存然而，Ct可能使用色氨酸前体吲哚来挽救色氨酸的合成和逃逸 IFN-γ介导的杀伤。到目前为止，在人类中缺乏支持这种机制的数据。识别免疫 人类抗Ct保护的相关性，具有明确定义的Ct感染和清除数据的队列研究 是必要的。乔丹医生可以获得外周血单核细胞（PBMC）和宫颈阴道灌洗 来自具有实验室确认的Ct感染的> 400名女性的独特队列的CVL，其中> 80名女性可能具有 对Ct的保护性免疫力证明了他们（1）在返回治疗前自然清除Ct感染 和（2）与持续感染的女性相比，随后发生Ct再感染的可能性低4倍 在治疗的时候。有了这些宝贵的标本和研究培训计划的指导下， 乔丹博士是一个杰出的指导团队，能够很好地研究IFN-γ介导的细胞免疫的作用。 反应和粘膜代谢物对Ct清除的影响。他的主要假设是， IFN-γ介导Ct感染的清除，其：（1）增加记忆性T细胞和NK细胞效应子 功能，和（2）促进一种抑制Ct存活的Escherichan耗尽的粘膜微环境， 吲哚依赖性色氨酸补救。他将研究80名清除Ct感染的妇女的标本 与80名持续感染的妇女匹配，（1）使用储存的PBMC研究IFN-γ（和 其他Th1细胞因子）在记忆性CD4+和CD8 + T细胞和NK细胞效应子应答中的作用（目的1） 和（2）使用储存的CVL标本研究IFN-γ介导的粘膜色氨酸耗竭是如何发生的， 测量CVL代谢物（例如，吲哚，犬尿氨酸），以鉴定依赖于和不依赖于色氨酸 与Ct清除相关的代谢途径（Aim 2）。这些研究将推动Ct疫苗的开发 通过鉴定疫苗应该靶向的特异性IFN-γ介导的细胞免疫应答， 测试疫苗的效力，并将扩大我们的知识，粘膜代谢途径参与Ct 清除，这可能会导致新的治疗方法。这项研究将得到职业发展的补充 包括免疫学和代谢组学培训的计划。完成这些活动将使乔丹博士 成为一名独立的医生科学家所需的工具。

PROJECT SUMMARY Dr. Jordan is a tenure-earning Assistant Professor at Indiana University School of Medicine whose career goal is to be an independent physician scientist studying human immune mechanisms of protection against Chlamydia trachomatis (Ct) infection, the most prevalent bacterial sexually transmitted infection worldwide and a major cause of reproductive tract morbidity. Control measures have failed to curb rising Ct infection rates and Ct vaccine development is hindered by a knowledge gap in human immune responses that confer Ct immunity. In animal models, interferon-gamma (IFN-γ) produced by T-cells and possibly natural killer (NK) cells, is required for chlamydia clearance, likely by depleting intracellular tryptophan; an essential amino acid for Ct survival. However, Ct may use the tryptophan precursor indole to salvage tryptophan synthesis and escape IFN-γ-mediated killing. To date, data to support this mechanism are lacking in humans. To identify immune correlates of human protection against Ct, cohort studies with clearly-defined Ct infection and clearance data are needed. Dr. Jordan has access to peripheral blood mononuclear cells (PBMCs) and cervicovaginal lavages (CVLs) from a unique cohort of >400 women with lab-confirmed Ct infection, in which >80 women may have protective immunity to Ct evidenced by their (1) natural clearance of Ct infection before returning for treatment and (2) being 4-fold less likely to have subsequent Ct reinfection, compared to women with persisting infection at the time of treatment. With access to these valuable specimens and a research training plan guided by an exceptional mentoring team, Dr. Jordan is well-positioned to study the role of IFN-γ-mediated cellular responses and the influence of mucosal metabolites on Ct clearance. His primary hypothesis is that natural clearance of Ct infection is mediated by IFN-γ, which: (1) increases memory T-cell and NK cell effector functions, and (2) promotes a tryptophan-depleted mucosal microenvironment that prohibits Ct survival via indole-dependent tryptophan salvage. He will study specimens from 80 women who cleared Ct infection matched to 80 women with persisting infection, and (1) use stored PBMCs to investigate the role of IFN-γ (and other Th1 cytokines) in memory CD4+ and CD8+ T-cell and NK cell effector responses in Ct clearance (Aim 1) and (2) use stored CVL specimens to investigate how IFN-γ-mediated mucosal tryptophan depletion occurs by measuring CVL metabolites (e.g., indole, kynurenine) to identify tryptophan-dependent and independent metabolic pathways associated with Ct clearance (Aim 2). These studies will advance Ct vaccine development by identifying specific IFN-γ-mediated cellular immune responses that vaccines should target, biomarkers to test vaccine efficacy, and will expand our knowledge of the mucosal metabolic pathways involved in Ct clearance, which may lead to new treatments. The research will be complemented by a career development plan that includes immunology and metabolomics training. Completion of these activities will equip Dr. Jordan with the needed tools to become an independent physician scientist.