Human Genetic Variance and Cellular Responses to Sexually Transmitted Infections

项目总结 性传播感染引起的炎症反应对生殖器官的损害可导致严重的 盆腔炎、宫外孕、不孕症等并发症。多重环境 因素包括感染的菌株、感染的剂量和频率以及微生物的组成 泌尿生殖道的社区有助于疾病表现的严重性和随之而来的后遗症。 同样，与其他性传播病原体的混合感染可能会协同作用，使疾病恶化。 最后，宿主遗传可能在感染的易感性和随后的感染中起着重要作用。 免疫病理学。该项目将解决人类基因多态所起的作用， 调节细胞对沙眼衣原体的相互作用和反应。 淋病和阴道微生物区系组成。我们将识别和表征基因变异 通过采用两种并行和互补的方法来影响性传播感染。首先，我们将使用一个发现平台来 被称为高主(高通量体外人类)的细胞特征的全基因组关联研究 药敏试验)。Hi-host结合了对来自数百个细胞的表型的精确测量 具有全基因组关联的正常的、基因分型的个体，以确定构成 表型变异。此外，我们建议扩展Hi-host框架以检查联合感染是如何 微生物群可以协同或拮抗地作用于免疫反应，以及人类基因如何 差异可以调节这些效应。第二，我们将开展临床特征和预后的GWAS使用 被刺伤的人群。这种双重方法将允许研究受控者和受控者之间的人类基因变异 Hi-host相同感染的实验环境和临床上更相关但更复杂的环境 病人。 我们预测，由Hi-host和刺痛队列的GWAs确定的SNPs的重叠将突出人类 影响细胞感染表型和临床表型及预后的变异。因此，我们将 不仅确定哪些人类基因变异与性传播感染的易感性有关，而且还 中间表型(如细胞因子水平、miRNA和微生物区系组成)可能 对改变的生理负责。这将有助于识别生物标记物和可能的药物靶标， 以及可能从靶向治疗中受益最大的特定遗传群体。

PROJECT SUMMARY 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.