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

干扰素-γ 在清除女性沙眼衣原体感染中的作用

• 批准号: 10160813
• 负责人: Stephen J. Jordan
• 金额: $ 18.42万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-21 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160813
• 关键词: Animal Model; Antigens; Bacteria; Biological Assay; CD3 Antigens; CD8-Positive T-Lymphocytes; Catabolism; Cells; Chlamydia; Chlamydia trachomatis; Cohort Studies; Complement; Data; Development Plans; Effector Cell; Environment; Essential Amino Acids; FCGR3B gene; Frequencies; Future; Goals; Granzyme; Growth; High Pressure Liquid Chromatography; Human; Immune; Immune response; Immunity; Immunofluorescence Immunologic; Immunology; In Vitro; Indiana; Indoles; Infection; Interferon Type II; Interleukin-2; Irrigation; Jordan; Knowledge; Kynurenine; Lead; Measures; Mediating; Memory; Mentors; Metabolic Pathway; Morbidity - disease rate; Mucous Membrane; NK Cell Activation; Natural Killer Cells; Pathway Analysis; Peripheral Blood Mononuclear Cell; Persons; Physicians; Population; Positioning Attribute; Production; Research; Research Training; Risk; Role; Scientist; Sexually Transmitted Diseases; Specimen; Stains; T memory cell; T-Lymphocyte; TNF gene; Testing; Time; Training; Tryptophan; Universities; Vaccines; Woman; career; career development; cervicovaginal; chlamydia vaccine; chronic infection; cohort; cytokine; cytotoxicity; infection rate; liquid chromatography mass spectrometry; medical schools; metabolomics; perforin; peripheral blood; professor; programs; reproductive morbidity; reproductive tract; response; screening; targeted biomarker; tool; tubal infertility; vaccine development; vaccine efficacy; vaccine evaluation; vaccine response

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.

项目总结 乔丹博士是印第安纳大学医学院获得终身教职的助理教授，他的职业目标是 是一名研究人类免疫机制的独立内科科学家 沙眼衣原体(CT)感染是全球最流行的细菌性性传播感染， 生殖道疾病的一个主要原因。控制措施未能遏制不断上升的CT感染率和 CT疫苗的开发受到人类免疫反应中授予CT免疫的知识鸿沟的阻碍。 在动物模型中，T细胞和可能的自然杀伤细胞(NK细胞)产生的干扰素-γ是 衣原体清除所必需的，可能是通过消耗细胞内的色氨酸；CT的一种必需氨基酸 生死存亡。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 干扰素-γ介导的杀伤作用。到目前为止，在人类身上还缺乏支持这种机制的数据。识别免疫 人类对CT的保护作用，队列研究与明确定义的CT感染和清除数据的相关性 都是需要的。乔丹博士可以使用外周血单个核细胞(PBMC)和宫颈阴道灌洗液 (CVL)来自400名患有实验室确认的CT感染的女性，其中80名女性可能患有 对CT的保护性免疫：(1)回国治疗前CT感染的自然清除 和(2)与持续感染的女性相比，随后再次感染CT的可能性低4倍 在治疗的时候。通过获取这些有价值的标本和一份由 卓越的指导团队，乔丹博士很好地研究了干扰素-γ介导的细胞的作用 粘膜代谢物对CT清除的反应和影响。他的主要假设是自然的 Ct感染的清除是由干扰素-γ介导的，它：(1)增加记忆T细胞和NK细胞效应 功能，以及(2)促进色氨酸耗竭的粘膜微环境，通过 依赖吲哚的色氨酸回收。他将研究80名清除了CT感染的女性的样本 与80名持续感染的女性配对，以及(1)使用存储的PBMC来研究干扰素-γ的作用(和 其他Th1细胞因子)在CT清除中记忆中的CD4+和CD8+T细胞和NK细胞效应反应(目标1) 和(2)使用储存的CVL标本来研究干扰素-γ介导的粘膜色氨酸耗竭是如何通过以下方式发生的 测定CVL代谢物(如吲哚、犬尿氨酸)以确定色氨酸依赖和非依赖 与Ct清除相关的代谢途径(目标2)。这些研究将推动CT疫苗的开发 通过识别疫苗应该靶向的特定干扰素-γ介导的细胞免疫反应，生物标记物 测试疫苗的效力，并将扩大我们对参与CT的粘膜代谢途径的了解 清除，这可能导致新的治疗方法。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。这些活动的完成将使乔丹博士 拥有成为一名独立内科科学家所需的工具。