In the battleground of an infection site, both the host cells and the microbes employ complex signaling mechanisms and weaponry to destabilize, neutralize or kill the other. Identifying and understanding these biomarkers of infection and disease are the short and long-term research goals of this Cooperative Research Center (CRC). The anticipated impact will be to reduce the incidence of sexually transmitted infections and diseases (STIs &STDs) in humans worldwide. This is a large scale challenge: in the United States, Chlamydia trachomatis (CT) genital infections are the most frequently reported bacterial infectious disease with an estimated 2.8M cases yearly. Likewise there are an estimated 820,000 cases of Neisseria gonorrhoeae (GC) each year. The sequelae of infections and co-infections caused by these two pathogens are insidious and account for the majority of the 750,000 annual cases of pelvic inflammatory disease (PID) in the United States, a precursor to life-threatening ectopic pregnancy and tubal factor infertility (TFI) in women. Thus, research to prevent, control and treat these STIs will provide broad health and economic benefits. We hypothesize that: a) the genetic variance of the infected host, the genetic diversity of the infecting pathogen(s), and the composition and function of the resident microbiota directly impact the evolution of STIs and could be biomarkers of disease severity or protection from STIs;b) genes, RNAs and proteins that are expressed or produced by the host, the pathogens, and/or the genital microbiota in response to one another are biomarkers of a specific type of STI or STD.
The aim of the CRC is therefore to identify host, pathogen and/or microbiota biomarkers of STIs that may reveal mechanisms of pathogenesis and therapeutic or diagnostic targets that can be exploited for the development of translational curative or prophylactic interventions that have a direct impact in public health. To test these hypotheses and realize these objectives, this CRC, "Eco-Pathogenomics of Sexually Transmitted Infections" (EPSTI), will build on data acquired by the parent CRC, "Eco-Pathogenomics of Chlamydial Reproductive Tract Infection", a Chlamydia-centric program that laid the methodological and conceptual foundations of EPSTI. Within EPSTI, STING (STI Network Groups), consisting of multiple networks of sexual partners, will be leveraged to examine the triangular relationship between human genetic variance, CT, GC infections and co-infections, and microbiota composition among partners with distinct infection outcomes. The experimental approach will essentially be a systems biology strategy focused on the identification of biomarkers of genital/reproductive infection and disease and are eminently amenable to translational applications in clinical and public health. These are expected to include predictive diagnosis for individuals at greatest risk of STI and STD based on their biological and microbiome characteristics, development of sensitive and specific point-of-care diagnostic tests and highly specific targets for vaccine development.
The Program aims to 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 the NIH mission as it ultimately aims at promoting health, reducing risk to unintended adverse sequelae of sexually transmitted disease (STI) and improving the quality of life for men and women who are at risk of STIs. Project 1: Human Genetic Variance and Cellular Responses to Sexually Transmitted Infections Project Leader: Dennis Ko DESCRIPTION (provided by applicant): 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 infectio 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.
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