HLA Fine Mapping to Elucidate S. aureus Susceptibility

本申请使用大的人类前瞻性队列来鉴定宿主的遗传决定因素， 金黄色葡萄球菌菌血症（SAB），一种常见的和潜在的致命感染的易感性。的 本研究中要检验的总体假设是，人白细胞抗原中的特定变体 (HLA)II类区域是人类对SAB易感性的重要决定因素，并且这些 可以通过研究大量的、特征明确的患者群体来确定决定因素。这种假设是 基于我们的两项独立研究，1）确定了HLA变异的全基因组显著关联， II类，S的风险增加。金黄色葡萄球菌感染的欧洲血统的个人;和2）确定了一个 在非裔美国患者中，欧洲来源的HLA II类变异体与SAB的全基因组关联在 在这项研究中，我们将进一步完善HLA II类区域中SAB的遗传风险因素。我们创建 色葡萄aureus Bacteremia Group（SABG）是世界上最大的配对人类DNA集合之一， SAB患者血液中的细菌我们组建了一个经验丰富的多学科团队， 独特的SABG队列资源，最先进的基因分型技术和创新的体内模型系统， 突破了这个领域的界限我们提出三个具体目标。在目标1中，我们将确定遗传风险 HLA-II类中的因子用于发展SAB，使用高密度基因分型和插补来饱和HLA 在2300名SAB患者和2300名未受影响的对照中， SABG队列。在目标2中，我们将研究HLA II类等位基因和单倍型与 在2300例SAB基因分型为SA 1的复杂SAB患者中， 基因型对复杂性SAB风险的影响。金黄色葡萄球菌从所有的 2300例SAB患者。通过这种方法，我们将检测复杂SAB是否与HLA II类相关， 等位基因和单倍型被血流S的特定遗传谱系修饰。金黄色。在目标3中， 将评估HLA等位基因的功能后果，确定在目标1，目标2，和我们以前的研究。 通过体内和体外实验进行研究。我们将评估特定的HLA II类等位基因是否显著 改变宿主T细胞对S.金黄色葡萄球菌使用1）S.金黄色葡萄球菌脓毒症转基因小鼠模型 人HLA II类等位基因;和2）使用S.金黄色葡萄球菌感染抗原 呈递细胞表达不同的HLA等位基因。该项目的长期目标是：（1）充分 表征患有SAB的个体和未受影响的对照的多种族样品中的HLA变异;和2） 为本项目中鉴定的HLA II类变异体的临床相关性提供生物学证据。采取 总之，这一建议的影响是增加我们对宿主遗传变异如何影响 S.金黄色葡萄球菌感染阐明了S.金黄色 感染将改善我们对这一紧急医疗危机的理解、治疗和预防。

This application uses a large human prospective cohort to identify the host genetic determinants of susceptibility to Staphylococcus aureus bacteremia (SAB), a common and potentially lethal infection. The overarching hypothesis to be tested in this study is that specific variants in the Human Leukocyte Antigen (HLA) class II region are important determinants of susceptibility to SAB in humans, and that these determinants can be identified by studying large, well-characterized cohorts of patients. This hypothesis is based upon our two separate studies that 1) identified genome-wide significant associations of variants in HLA class II with an increased risk for S. aureus infections in individuals of European descent; and 2) identified a genome-wide association of European-derived HLA Class II variants and SAB in African-American patients. In the proposed study, we will further refine the genetic risk factors for SAB in the HLA class II region. We created the S. aureus Bacteremia Group (SABG), one of the world’s largest collections of paired human DNA and bloodstream bacteria from patients with SAB. We assembled an experienced multidisciplinary team to link the unique SABG cohort resources to state-of-the-art genotyping technology and innovative in vivo model systems, pushing the boundaries of the field. We propose three Specific Aims. In Aim 1, we will identify the genetic risk factors in HLA class II for developing SAB, using high-density genotyping and imputation to saturate the HLA region in 2300 individuals with SAB and 2300 unaffected controls enrolled in the longitudinal, prospective SABG cohort. In Aim 2, we will examine the association of HLA class II alleles and haplotypes with complicated SAB in the 2300 patients with SAB genotyped in SA1, and consider the impact of bacterial genotype on the risk for complicated SAB by genotyping the bloodstream S. aureus isolates from all of the 2300 SAB patients. In this way, we will test whether the association of complicated SAB with HLA class II alleles and haplotypes is modified by the specific genetic lineage of the bloodstream S. aureus. In Aim 3, we will evaluate the functional consequences of the HLA alleles identified in Aim 1, Aim 2, and in our previous studies with in vivo and in vitro experiments. We will evaluate whether specific HLA class II alleles significantly alter host T cell responses to S. aureus using 1) a S. aureus sepsis model in transgenic mice expressing human HLA class II alleles; and 2) stimulation of T cells from SAB patients using S. aureus infected antigen presenting cells expressing different HLA alleles. The long-term objectives of this project are 1) to fully characterize HLA variation in a multi-ethnic sample of individuals with SAB and unaffected controls; and 2) to provide biological evidence for the clinical relevance of the HLA class II variants identified in this project. Taken together, the impact of this proposal is to increase our understanding of how host genetic variation influences the initiation and severity of S. aureus infections. Elucidating the genetic basis of susceptibility to S. aureus infection will improve our understanding, treatment, and prevention of this urgent unmet medical crisis.