HLA Fine Mapping to Elucidate S. aureus Susceptibility

HLA 精细作图阐明金黄色葡萄球菌敏感性

• 批准号: 10490895
• 负责人: Vance G. Fowler
• 金额: $ 78.06万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490895
• 关键词: Admixture; African American; Alleles; Antigen-Presenting Cells; Antigenic Variation; Bacteremia; Bacteria; Bacterial Infections; Biological; Biological Models; Biological Process; Blood Circulation; Collection; Endocarditis; Enrollment; European; Frequencies; Genetic; Genetic Determinism; Genetic Variation; Genotype; Goals; HLA Antigens; Haplotypes; Histocompatibility Antigens Class II; Human; Immune response; In Vitro; Individual; Infection; Link; Medical; Modeling; Multi-Drug Resistance; Nucleotides; Osteomyelitis; Patients; Predisposition; Prevention; Prospective cohort; Proteins; Public Health; Research Personnel; Resources; Risk; Sampling; Sepsis; Severities; Soft Tissue Infections; Staphylococcus aureus; Staphylococcus aureus infection; Streptococcus pyogenes; Superantigens; T cell response; T-Lymphocyte; Testing; Transgenic Mice; United States; Variant; Work; base; biobank; clinically relevant; cohort; deep sequencing; density; experience; experimental study; genetic risk factor; genetic variant; genome wide association study; genome-wide; genotyping technology; human DNA; improved; in vivo; in vivo Model; innovation; methicillin resistant Staphylococcus aureus; multi-ethnic; multidisciplinary; prospective

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.

该应用使用大型人类前瞻性队列来识别 对金黄色葡萄球菌细菌（SAB）的敏感性，一种常见且潜在的致命感染。这 在这项研究中要检验的总体假设是人类白细胞抗原中的特定变体 （HLA）II类区域是对人类SAB敏感性易感性的重要决定者，并且 可以通过研究大型，良好的患者同类群来识别决定因素。这个假设是 基于我们的两项独立研究，即1）鉴定了HLA中跨基因组的显着关联 欧洲血统个体中金黄色葡萄球菌感染风险增加的II级； 2）确定 非裔美国人患者的欧洲HLA II类变体和SAB的全基因组全基因组关联。在 拟议的研究，我们将进一步完善HLA II类区域中SAB的遗传危险因素。我们创建了 金黄色葡萄球菌菌血症组（SABG）是世界上最大的配对人类DNA和 SAB患者的血液细菌。我们组建了一个经验丰富的多学科团队，以联系 独特的SABG队列资源用于最先进的基因分型技术和体内模型系统创新的资源， 推动该领域的边界。我们提出了三个具体目标。在AIM 1中，我们将确定遗传风险 HLA II类用于开发SAB的因素，使用高密度的基因分型和插入HLA饱和的因素 纵向，前瞻性的2300名患有SAB和2300个未受影响对照的人的区域 SABG队列。在AIM 2中，我们将研究HLA II类等位基因和单倍型与 SA1中SAB基因分型的2300例SAB患者的复杂SAB，并考虑细菌的影响 通过基因分型将血液S.金黄色葡萄球菌分离出来的基因型，来自所有的sab。 2300名SAB患者。这样，我们将测试复杂的SAB与HLA II类的关联是否 等位基因和单倍型通过血流金黄色葡萄球菌的特定遗传谱系进行了修饰。在AIM 3中，我们 将评估在AIM 1，AIM 2和我们以前的AIM 1中确定的HLA等位基因的功能后果 体内和体外实验的研究。我们将评估特定的HLA II类等位基因是否显着 在转基因小鼠中使用1）A.金黄色葡萄球菌对金黄色葡萄球菌的反应 人类HLA II类等位基因； 2）使用金黄色葡萄球菌感染的抗原刺激SAB患者的T细胞 呈现表达不同HLA等位基因的细胞。该项目的长期目标是1）完全 表征具有SAB和未受影响对照的个体的多民族样本中的HLA变化；和2）到 提供生物学证据，证明该项目中发现的HLA II类变体的临床相关性。拍摄 总之，该提案的影响是增加我们对宿主遗传变异如何影响的理解 金黄色葡萄球菌感染的主动性和严重程度。阐明对金黄色葡萄球菌的易感性的遗传基础 感染将改善我们对这种紧急未受医疗危机的理解，治疗和预防。