Natural History of Chlamydia trachomatis genital tract infection in women

Chlamydia trachomatis is a well-recognized PID pathogen for which no vaccine is available. Women are at risk for reproductive sequelae when infection ascends into the upper reproductive tract, driving inflammatory processes that trigger immune pathology. However, the bacterial and/or host factors that govern ascension and subsequent pathology remain unknown. Our long-term goal is to identify biomarkers that identify women at risk for reproductive morbidity or correlate with protective immunity. We and others have established that susceptibility to human chlamydial genital infection is mediated by pathogen abundance, co-infection, oral contraceptives and cervicovaginal microbiota. The overall objective of this proposal is to identify cervical discriminators of asymptomatic, ascending chlamydial infection and endometritis in women. The central hypothesis is that overall risk for ascending infection is modulated by local host inflammatory responses, pathogen fitness and environmental factors mediated by the cervicovaginal microbiome. Our rationale is that identifying these factors will accelerate rational vaccine design and testing. In a pilot study of women at high risk for STIs, we demonstrated the potential for unbiased characterization of host, pathogen and microbiome interactions using transcriptomics and determined that a single cervical specimen was sufficient to detect clustered host transcriptional profiles reflecting microbiome differences and STI infection. Guided by strong preliminary data and leveraging ongoing NIH funded research, the following four specific aims will test our hypothesis: 1) Profile cervical immune response with respect to ascending infection and susceptibility to reinfection; 2) Profile chlamydial transcriptional activity associated with ascending infection; 3) Profile transcriptionally active microflora in Chlamydia-infected women to determine how these complex microbial communities modulate ascending infection; and 4) Integrate host, pathogen and microbiome responses to determine key pathways controlling outcome. The first aim will profile cervical inflammatory responses and immune cell populations from women with local infection or upper tract involvement in a cohort of highly-exposed women (TRAC2). We will transcriptionally profile the chlamydial strains causing their infections and use metatranscriptomics to characterize the contribution of the cervicovaginal microbiome. Finally, we will use robust biostatistical approaches to improve and expand our understanding of key chlamydia–host interactions that modulate infection outcomes, drive disease and establish protective immunity. The research proposed is innovative, in our opinion, because it will implement a comprehensive, non-biased approach to the identification of molecular biomarkers in a highly disease-relevant clinical population. The proposed research is significant because it is expected to translate directly to anti-chlamydial vaccine evaluation in humans and to have broad importance for diagnosis and for evaluation of novel therapeutics.