Damage to reproductive organs as a result of inflammatory responses to STIs can lead to severe complications such as pelvic inflammatory disease, ectopic pregnancy and infertility. Multiple environmental factors including the infecting strain, dose and frequency of infections, and composition of the microbial communities in the urogenital tract contribute to the severity of disease manifestation and ensuing sequelae. Similarly, co-infection with other sexually transmitted pathogens may act synergistically to worsen disease. Finally, host genetics likely plays an important role in susceptibility to infection and ensuing immunopathologies. This project will address the role played by human genetic polymorphisms that regulate cellular interactions and responses to C. trachomatis alone or in the context of N. gonorrhoeae and vaginal microbiota components. We will identify and characterize genetic variants that affect STIs by applying two parallel and complementary approaches. First, we will use a discovery platform for genome-wide association studies (GWAS) of cellular traits called Hi-HOST (high throughput human in vitro susceptibility testing). Hi-HOST combines precise measurement of phenotypes in cells derived from hundreds of normal, genotyped individuals with genome-wide association to identify genetic differences that underlie the phenotypic variation. Furthermore, we propose to extend the Hi-HOST framework to examine how co-infection and the microbiota can act synergistically or antagonistically on the immune response and how human genetic differences can modulate these effects. Second, we will carry out GWAS of clinical traits and outcomes using the STING cohort. This dual approach will allow for study of human genetic variation in both the controlled experimental setting of identical infections with Hi-HOST and the more clinically relevant but complex setting of patients. We predict that overlap of SNPs identified by Hi-HOST and GWAS of the STING cohort will highlight human variation affecting both cellular infection phenotypes and clinical phenotypes and outcomes. Thus, we will determine not only which human genetic variants are associated with susceptibility to STIs but also intermediate phenotypes (such as cytokine levels, miRNA, and microbiota composition) that are likely responsible for the altered physiology. This will facilitate identification of biomarkers and possible drug targets, as well as specific genetic populations that might benefit most from targeted therapies.
The identification of human genetic variants that contribute to the host/STI pathogen/microbiome interactions will provide a fundamental understanding of the molecular mechanisms underlying susceptibility to infection and ensuing risks to immunopathologies. Furthermore, these genetic variants will provide novel biomarkers to identify individuals at greatest risk to infection, recurrence and disease, such that appropriate therapies are applied. This research is relevant to NIH mission of promoting health by reducing risk to unintended adverse consequences of STI and improving the quality of life for men and women who are at risk.
|Mendes-Soares, Helena; Suzuki, Haruo; Hickey, Roxana J et al. (2014) Comparative functional genomics of Lactobacillus spp. reveals possible mechanisms for specialization of vaginal lactobacilli to their environment. J Bacteriol 196:1458-70|
|Bavoil, Patrik M (2014) What's in a word: the use, misuse, and abuse of the word "persistence" in Chlamydia biology. Front Cell Infect Microbiol 4:27|
|Bavoil, Patrik M; Byrne, Gerald I (2014) Analysis of CPAF mutants: new functions, new questions (the ins and outs of a chlamydial protease). Pathog Dis 71:287-91|
|Hickey, Roxana J; Forney, Larry J (2014) Gardnerella vaginalis does not always cause bacterial vaginosis. J Infect Dis 210:1682-3|
|Adams, Nancy E; Thiaville, Jennifer J; Proestos, James et al. (2014) Promiscuous and adaptable enzymes fill "holes" in the tetrahydrofolate pathway in Chlamydia species. MBio 5:e01378-14|
|Brotman, Rebecca M; Ravel, Jacques; Bavoil, Patrik M et al. (2014) Microbiome, sex hormones, and immune responses in the reproductive tract: challenges for vaccine development against sexually transmitted infections. Vaccine 32:1543-52|
|Hovis, Kelley M; Mojica, Sergio; McDermott, Jason E et al. (2013) Genus-optimized strategy for the identification of chlamydial type III secretion substrates. Pathog Dis 69:213-22|
|Vorimore, Fabien; Hsia, Ru-Ching; Huot-Creasy, Heather et al. (2013) Isolation of a New Chlamydia species from the Feral Sacred Ibis (Threskiornis aethiopicus): Chlamydia ibidis. PLoS One 8:e74823|
|Yeruva, Laxmi; Spencer, Nicole; Bowlin, Anne K et al. (2013) Chlamydial infection of the gastrointestinal tract: a reservoir for persistent infection. Pathog Dis 68:88-95|
|Fisher, Derek J; Fernández, Reinaldo E; Maurelli, Anthony T (2013) Chlamydia trachomatis transports NAD via the Npt1 ATP/ADP translocase. J Bacteriol 195:3381-6|
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