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.

Public Health Relevance

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.

National Institute of Health (NIH)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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University of Maryland Baltimore
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Ravel, Jacques; Brotman, Rebecca M (2016) Translating the vaginal microbiome: gaps and challenges. Genome Med 8:35
France, Michael T; Mendes-Soares, Helena; Forney, Larry J (2016) Genomic Comparisons of Lactobacillus crispatus and Lactobacillus iners Reveal Potential Ecological Drivers of Community Composition in the Vagina. Appl Environ Microbiol 82:7063-7073
Pittman, Kelly J; Glover, Luke C; Wang, Liuyang et al. (2016) The Legacy of Past Pandemics: Common Human Mutations That Protect against Infectious Disease. PLoS Pathog 12:e1005680
Robinson, Courtney K; Brotman, Rebecca M; Ravel, Jacques (2016) Intricacies of assessing the human microbiome in epidemiologic studies. Ann Epidemiol 26:311-21
Dareng, E O; Ma, B; Famooto, A O et al. (2016) Prevalent high-risk HPV infection and vaginal microbiota in Nigerian women. Epidemiol Infect 144:123-37
Nunn, Kenetta L; Forney, Larry J (2016) Unraveling the Dynamics of the Human Vaginal Microbiome. Yale J Biol Med 89:331-337
Neuendorf, Elizabeth; Gajer, Pawel; Bowlin, Anne K et al. (2015) Chlamydia caviae infection alters abundance but not composition of the guinea pig vaginal microbiota. Pathog Dis 73:
Wang, Liuyang; Oehlers, Stefan H; Espenschied, Scott T et al. (2015) CPAG: software for leveraging pleiotropy in GWAS to reveal similarity between human traits links plasma fatty acids and intestinal inflammation. Genome Biol 16:190
Breshears, Laura M; Edwards, Vonetta L; Ravel, Jacques et al. (2015) Lactobacillus crispatus inhibits growth of Gardnerella vaginalis and Neisseria gonorrhoeae on a porcine vaginal mucosa model. BMC Microbiol 15:276
Nunn, Kenetta L; Wang, Ying-Ying; Harit, Dimple et al. (2015) Enhanced Trapping of HIV-1 by Human Cervicovaginal Mucus Is Associated with Lactobacillus crispatus-Dominant Microbiota. MBio 6:e01084-15

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