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

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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.