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.
|Palmer, Allison; Criss, Alison K (2018) Gonococcal Defenses against Antimicrobial Activities of Neutrophils. Trends Microbiol 26:1022-1034|
|Schroeder, Holly A; Nunn, Kenetta L; Schaefer, Alison et al. (2018) Herpes simplex virus-binding IgG traps HSV in human cervicovaginal mucus across the menstrual cycle and diverse vaginal microbial composition. Mucosal Immunol 11:1477-1486|
|Ragland, Stephanie A; Humbert, Mar?a V; Christodoulides, Myron et al. (2018) Neisseria gonorrhoeae employs two protein inhibitors to evade killing by human lysozyme. PLoS Pathog 14:e1007080|
|van Houdt, Robin; Ma, Bing; Bruisten, Sylvia M et al. (2018) Lactobacillus iners-dominated vaginal microbiota is associated with increased susceptibility to Chlamydia trachomatis infection in Dutch women: a case-control study. Sex Transm Infect 94:117-123|
|Cornejo, Omar E; Hickey, Roxana J; Suzuki, Haruo et al. (2018) Focusing the diversity of Gardnerella vaginalis through the lens of ecotypes. Evol Appl 11:312-324|
|Tyssen, David; Wang, Ying-Ying; Hayward, Joshua A et al. (2018) Anti-HIV-1 Activity of Lactic Acid in Human Cervicovaginal Fluid. mSphere 3:|
|Tachedjian, Gilda; O'Hanlon, Deirdre E; Ravel, Jacques (2018) The implausible ""in vivo"" role of hydrogen peroxide as an antimicrobial factor produced by vaginal microbiota. Microbiome 6:29|
|Noyes, Noelle; Cho, Kyu-Chul; Ravel, Jacques et al. (2018) Associations between sexual habits, menstrual hygiene practices, demographics and the vaginal microbiome as revealed by Bayesian network analysis. PLoS One 13:e0191625|
|Wang, Liuyang; Pittman, Kelly J; Barker, Jeffrey R et al. (2018) An Atlas of Genetic Variation Linking Pathogen-Induced Cellular Traits to Human Disease. Cell Host Microbe 24:308-323.e6|
|Smith, Steven B; Ravel, Jacques (2017) The vaginal microbiota, host defence and reproductive physiology. J Physiol 595:451-463|
Showing the most recent 10 out of 54 publications