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: 10404647
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404647
• 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 immunogenicity

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

项目成果

Natural Clearance of Chlamydia trachomatis Infection Is Associated With Distinct Differences in Cervicovaginal Metabolites.

沙眼衣原体感染的自然清除与宫颈阴道代谢物的明显差异相关。

• DOI: 10.1093/infdis/jiad155
• 发表时间: 2023
• 期刊: The Journal of infectious diseases
• 作者: Jordan,StephenJ;Wilson,Landon;Ren,Jie;Gupta,Kanupriya;Barnes,Stephen;Geisler,WilliamM
• 通讯作者: Geisler,WilliamM

Case Report: Candida dubliniensis as a Cause of Chronic Meningitis.

• DOI: 10.3389/fneur.2020.601242
• 发表时间: 2020
• 期刊: Frontiers in neurology
• 影响因子: 3.4
• 作者: Tahir M;Peseski AM;Jordan SJ
• 通讯作者: Jordan SJ

Evaluation of Clinical, Gram Stain, and Microbiological Cure Outcomes in Men Receiving Azithromycin for Acute Nongonococcal Urethritis: Discordant Cures Are Associated With Mycoplasma genitalium Infection.

• DOI: 10.1097/olq.0000000000001509
• 发表时间: 2022-01-01
• 期刊: Sexually transmitted diseases
• 影响因子: 3.1
• 作者: Toh E;Gao X;Williams JA;Batteiger TA;Coss LA;LaPradd M;Ren J;Geisler WM;Xing Y;Dong Q;Nelson DE;Jordan SJ
• 通讯作者: Jordan SJ