Host Susceptibility to S. aureus

描述（由申请人提供）：本次竞争性更新的总体目标是进一步了解为什么有些个体会发生金黄色葡萄球菌感染；以及金黄色葡萄球菌菌血症（SAB）患者，为什么只有一些人出现不良后果？金黄色葡萄球菌感染率的增加和临床金黄色葡萄球菌菌株对所有现有抗生素耐药的鉴定，要求对宿主对这种新出现的病原体反应的遗传基础有更多的了解。在此应用中要测试的具体假设是，可识别的宿主遗传因素是金黄色葡萄球菌感染易感性的重要决定因素。这一假设是基于1)不同种族人群（包括非裔美国人）的SAB发病率较高；2)特殊罕见遗传病患者SAB发生率较高；3)我们在近交小鼠中对金黄色葡萄球菌不同遗传易感性的原始应用发现。尽管人类和分子遗传学最近取得了进展，但尚未发表关于人类对金黄色葡萄球菌遗传易感性的大规模研究。这主要是由于缺乏从金黄色葡萄球菌感染患者中收集的具有良好特征的DNA和相应的细菌分离物。我们的团队创建了金黄色葡萄球菌菌血症组（SABG），这是世界上最大的配对人类DNA和SAB患者血液分离物的集合之一。在我们最初的R01发现的基础上，我们的更新将独特的SABG资源与最先进的技术相结合，并与人类遗传学权威机构进行强有力的合作，以寻求在SAB患者中发现新的遗传变异的多方面方法。为此，我们提出了四个具体目标：1)在小鼠脓毒症模型中确定与金黄色葡萄球菌感染易感性相关的候选基因；2)利用混合定位技术鉴定非洲裔美国人（AA）金黄色葡萄球菌感染易感性相关候选基因；3)通过外显子组测序，对SAB（特别是复杂SAB）中包含罕见、功能性、编码序列变异的基因进行鉴定和优先排序；4)在整个SABG队列（1200例/1200例对照）中，检验原始R01中发现的现有候选基因与Aims 1-3中发现的新候选基因的相关性。该项目的长期目标是：1)确定对金黄色葡萄球菌敏感的基因；2)探讨这些基因在金黄色葡萄球菌菌血症患者中的临床意义；3)最终利用这些基因确定控制金黄色葡萄球菌感染的新干预措施。这笔拨款的成果将包括加深对金黄色葡萄球菌遗传易感性在确定感染的发展和严重程度方面的作用的了解。当前应用的全部价值还包括，如果宿主基因型和临床结果之间的联系（只有使用如此庞大且特征明确的基因组才能确定）对整个研究界的潜在益处

DESCRIPTION (provided by applicant): The overall goal of this competitive renewal is to further understand why some individuals develop Staphylococcus aureus infection; and of those with S. aureus bacteremia (SAB), why only some develop adverse outcomes. Increasing rates of S. aureus infection and the identification of clinical S. aureus strains resistant to all currenly available antibiotics demand an increased understanding of the genetic basis for host response to this emerging pathogen. The specific hypothesis to be tested in this application is that identifiable host genetic factors are important determinants of susceptibility to S. aureus infection. This hypothesis is based upon 1) higher rates of SAB among ethnically distinct populations, including African Americans; 2) higher rates of SAB among patients with specific rare genetic conditions; and 3) our discovery in the original application of differing genetic susceptibility to S. aureus in inbred mice. Despite recent advances in human and molecular genetics, no large-scale studies of human genetic susceptibility to S. aureus have been published. This is largely due to the lack of a well-characterized collection of DNA and corresponding bacterial isolate from patients with S. aureus infection. Our group has created the S. aureus Bacteremia Group (SABG), one of the world's largest collections of paired human DNA and bloodstream isolates from patients with SAB. Building upon the discoveries of our original R01, our renewal combines the unique SABG resource with state of the art technology and strong collaborations with authorities in human genetics to pursue a multi-faceted approach to discovering novel genetic variants in patients with SAB. To do this we propose four Specific Aims: 1) identify candidate genes associated with susceptibility to S. aureus infection in a murine sepsis model; 2) identify candidate genes associated with susceptibility to S. aureus infection in African Americans (AA) using admixture mapping; 3) identify and prioritize genes containing rare, functional, coding sequence variants underlying SAB overall, and complicated SAB in particular, via exome sequencing; and 4) test the relevance of existing candidate genes discovered in the original R01 and new candidate genes in Aims 1-3 in the overall SABG cohort (1200cases/1200controls). The long-term objectives of this project are to: 1) identify genes responsible for susceptibility to S. aureus; 2) investigate the clinical importance of these genes in humans with S. aureus bacteremia; and 3) ultimately use these genes to identify novel interventions for the control of S. aureus infections. The products of this grant will include an increased understanding of the role of genetic susceptibility to S. aureus in determining the development and severity of infection. The full value of the current application also includes the potential benefit to the research community as a whole if links between host genotype and clinical outcome (only possible to identify using such a large and well-characterized collection of DNA from infected patients) can be defined. This work is critical to furthering the understanding of a crucial medical problem because: 1) S. aureus is an emerging pathogen, and 2) interventions to reduce S. aureus morbidity require a better knowledge of the determinants of both the development and severity of infection. Understanding the host genetic determinants of this disease will advance our understanding of staphylococcal pathogenesis and will enable key advances in protecting the public health from this pathogen. PUBLIC HEALTH RELEVANCE: competitive renewal is highly relevant to the health of the American Public, as it seeks to understand the pathophysiology of Staphylococcus aureus. S. aureus is one of the leading pathogens plaguing the American public. Rates of both infections and antibiotic resistance in S. aureus are increasing. These alarming trends indicate the possibility of a pathogen impervious to all currently approved therapy. This application seeks to improve our understanding of this persistent pathogen by pursuing the question, "Why do some, but not all patients develop S. aureus bacteremia, and of those infected, why do only some go on to develop life- threatening complications?" By increasing our understanding of the genetic basis of host response to S. aureus, this application could aid our ability to intervene in the disease process, focus healthcare resources onto S. aureus-infected patients at highest risk for complications, and lead to improved interventions and diagnostics.