Human Genetic Variance and Cellular Responses to Sexually Transmitted Infections

项目摘要 对性传播感染的炎症反应导致生殖器官受损， 盆腔炎、宫外孕和不孕症等并发症。多重环境 因素包括感染菌株、感染剂量和频率以及微生物的组成 泌尿生殖道中的微生物群落有助于疾病表现的严重性和随后的后遗症。 同样，与其他性传播病原体的合并感染可能会协同作用，使疾病恶化。 最后，宿主遗传学可能在感染易感性和随后的感染中起重要作用。 免疫病理学该项目将探讨人类遗传多态性所起的作用， 调节细胞相互作用和对C.沙眼衣原体单独或在N. 淋病和阴道微生物群成分。我们将识别和描述遗传变异， 通过应用两种平行且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， 细胞性状的全基因组关联研究（GWAS）称为Hi-HOST（高通量人类体外 敏感性测试）。Hi-HOST结合了对来自数百种细胞的表型的精确测量， 正常的，基因型个体与全基因组关联，以确定遗传差异， 表型变异此外，我们建议扩展Hi-HOST框架，以研究如何共同感染 微生物群可以协同或拮抗地作用于免疫反应， 差异可以调节这些影响。其次，我们将使用以下方法对临床特征和结局进行GWAS： STING队列。这种双重方法将允许研究人类遗传变异的控制， Hi-HOST相同感染的实验环境和更具临床相关性但复杂的 患者 我们预测STING队列的Hi-HOST和GWAS鉴定的SNP的重叠将突出人类 影响细胞感染表型和临床表型以及结果的变异。因此，我们将 不仅确定哪些人类遗传变异与STI易感性相关， 中间表型（如细胞因子水平，miRNA和微生物群组成）可能是 导致了生理变化这将有助于识别生物标志物和可能的药物靶点， 以及可能从靶向治疗中获益最多的特定遗传群体。

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.