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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI084044-06
Application #
8769308
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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
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
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

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