Epigenetic Determinants and Mechanisms Influencing Genital Chlamydia trachomatis Reinfection in African American Women

摘要/摘要：沙眼衣原体（Ct）感染是最常见的性传播细菌

Summary/Abstract: Chlamydia trachomatis (Ct) infection is the most prevalent sexually transmitted bacterial infection in the world. In the US alone, an estimated 3 million chlamydia cases are expected to occur annually. Ascending Ct infection in women can lead to pelvic inflammatory disease (PID), resulting in reproductive sequelae such as ectopic pregnancy, infertility, and chronic pelvic pain. Ct infections also disproportionally affect African Americans, who have almost a 6-fold higher Ct infection rate than Caucasians. Ct infection rates remain high despite active prevention and control efforts, and 20% of diagnosed patients are re-infected within one year, suggesting some infected persons do not develop sufficient immune protection. Reinfection contributes to continued Ct transmission and risk for Ct infection sequelae. Better prevention measures, such as a vaccine, are needed. The development of a Ct vaccine as well as other measures to prevent and control Ct infection in humans have been hindered in part by an incomplete understanding of the immune mechanisms that contribute to protection against Ct infections in humans. The goal of the research proposed in this application is to identify epigenetic alterations that influence immune responses and Ct reinfection risk. Several studies have shown that DNA methylation variation at individual CpG site has strong genetic component. The genetic effects on DNA methylation variations can be explained, in part, by SNPs located in close vicinity of the target CpG sites. Genetic variants that are associated with methylation variation are commonly referred to as methylation quantitative trait loci (meQTL), are crucial for understanding the epigenetic mechanisms underlying genotype-trait associations. DNA variants available from an existing ImmunoArray, together with DNAm profiling available from this proposal, will allow understanding of immunogenetic mechanisms that contribute to the pathogenesis of Ct reinfection. Central hypothesis: We hypothesize that altered epigenetic variation affects the immune response to Ct and therefore the risk for Ct reinfection. Furthermore, we hypothesize that identifying linked genetic and epigenetic variants that influence immune responses and Ct reinfection risk will allow us to pinpoint functional immunogenetic mechanisms. In Aim 1, we will conduct Epigenetic-Wide Association Analysis (EWAS) to identify epigenetic variations associated with immune responses that mediate protection against Ct reinfection in African American women. In Aim 2, we will use epigenetic, genetic, and immune response data to model how they influence Ct reinfection risk. In summary, our studies will investigate epigenetic mechanisms that modulate immune responses to Ct and influence Ct reinfection risk. To our knowledge, these will be the first studies of epigenetics in human Ct infection. We expect our studies will advance knowledge on how epigenetic and genetic factors influence immune responses and Ct reinfection risk, which should advance development of targeted interventions, such as a vaccine, to prevent and control Ct infection.