Abundant lactobacilli in the human vagina are thought to protect against invasion by non-indigenous bacteria, including sexually transmitted infections caused by Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC). The means by which this happens are not well understood. It could be that these exclusionary mechanisms are properties of the vaginal microbiome, features of the host immune system and physiology, or some combination of both. The goal of this project is to employ a systems biology approach to identify biomarkers of the vaginal and penile microbiome, the host and the pathogens that are associated with increased or decreased risks of infection by CT, GC or both. Project 3 of this research program will rely on samples collected by the Clinical Core C from STING networks of sex partners who have been exposed to and possibly infected by CT, GC, or both. In these networks we expect that about 20-40% of the participants will have been exposed to, but not infected by these pathogens. This will give us the unique opportunity to assess the role of the microbiome in preventing or facilitating infections by CT and GC. Our overarching hypothesis is that when pathogen transmission does not occur the genetic traits of the infecting pathogen(s) may be insufficient to overcome the host response or the exclusionary mechanisms of the microbiome environment;or that features of the microbiome are protective or induce a protective mucosal environment. In this project, we will build on these findings and use modern 'omic technologies to identify specific functional features of the vaginal and penile microbiota associated with susceptibility and resistance to infection and co- infection and the importance of host and pathogen genetic variation in this infection process, which will be done in collaboration with Projects 1 &2. We will achieve these goals by addressing three integrated specific aims:
Aim 1. Characterize the genomic variations in CT/GC in participants of the STING networks of sex partners;
Aim 2. Use 'omic approaches and system biology analysis characterize the molecular interactions between the host, the pathogens and the genital microbiota in discordant and concordant couples for CT/GC infections;
Aim 3. Validate and explore mechanistic explanations for how the microbiota prevent or facilitate infection by CT/GC using an in vitro three-dimensional model of endocervical epithelial cells. Our long-term goal is to leverage the information generated in this project to develop improved diagnostic methods, identify novel targets for new drug development and develop targeted and effective curative or preventive therapies, and ultimately, promote health, reduce risk to unintended adverse sequelae of STI and improve the quality of life for men and women who are at risk of STIs.
A molecular characterization of the host/STI pathogen/microbiome interactions will provide the fundamental knowledge needed to develop improved diagnostic methods, identify novel targets for new drug development and develop targeted and effective curative or preventive therapies. This research is relevant to NIH mission as it ultimately aims at promoting health, reducing risk to unintended adverse sequelae of STI and improving the quality of life for men and women who are at risk of STIs.
|Shannon, B; Yi, T J; Perusini, S et al. (2017) Association of HPV infection and clearance with cervicovaginal immunology and the vaginal microbiota. Mucosal Immunol 10:1310-1319|
|Tuddenham, Susan; Ghanem, Khalil G (2017) A microbiome variable in the HIV-prevention equation. Science 356:907-908|
|Oehlers, Stefan H; Flores, Maria Vega; Hall, Christopher J et al. (2017) A whole animal chemical screen approach to identify modifiers of intestinal neutrophilic inflammation. FEBS J 284:402-413|
|Shannon, B; Gajer, P; Yi, T J et al. (2017) Distinct Effects of the Cervicovaginal Microbiota and Herpes Simplex Type 2 Infection on Female Genital Tract Immunology. J Infect Dis 215:1366-1375|
|Smith, Steven B; Ravel, Jacques (2017) The vaginal microbiota, host defence and reproductive physiology. J Physiol 595:451-463|
|McClure, Erin E; Chávez, Adela S Oliva; Shaw, Dana K et al. (2017) Engineering of obligate intracellular bacteria: progress, challenges and paradigms. Nat Rev Microbiol 15:544-558|
|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|
|Ravel, Jacques; Brotman, Rebecca M (2016) Translating the vaginal microbiome: gaps and challenges. Genome Med 8:35|
|Van Lent, Sarah; De Vos, Winnok H; Huot Creasy, Heather et al. (2016) Analysis of Polymorphic Membrane Protein Expression in Cultured Cells Identifies PmpA and PmpH of Chlamydia psittaci as Candidate Factors in Pathogenesis and Immunity to Infection. PLoS One 11:e0162392|
|Nunn, Kenetta L; Forney, Larry J (2016) Unraveling the Dynamics of the Human Vaginal Microbiome. Yale J Biol Med 89:331-337|
Showing the most recent 10 out of 42 publications