Host Susceptibility to S. aureus

描述(由申请人提供)：本次竞争更新的总体目标是进一步了解为什么有些人会患上金黄色葡萄球菌感染；而在金黄色葡萄球菌菌血症(SAB)患者中，为什么只有一些人会出现不良后果。金黄色葡萄球菌感染率的增加和对目前所有抗生素耐药的临床金黄色葡萄球菌菌株的鉴定要求对这种新出现的病原体的宿主反应的遗传基础有更多的了解。在这一应用中要检验的具体假设是，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)不同种族人群中SAB的较高发病率，包括非裔美国人；2)特定罕见遗传病患者中SAB的较高发病率；以及3)我们在近交系小鼠中发现的对金黄色葡萄球菌不同遗传易感性的原始应用。尽管最近在人类和分子遗传学方面取得了进展，但还没有关于人类对金黄色葡萄球菌遗传易感性的大规模研究发表。这在很大程度上是由于缺乏从金黄色葡萄球菌感染患者身上收集的具有良好特征的DNA和相应的细菌分离株。我们团队创建了金黄色葡萄球菌菌血症组(SABG)，这是世界上最大的人类DNA配对和SAB患者血液分离的集合之一。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和与人类遗传学权威机构的强大合作结合在一起，寻求一种多方面的方法来发现SAB患者的新基因变异。为此，我们提出了四个具体目标：1)在小鼠脓毒症模型中识别与金黄色葡萄球菌感染易感性相关的候选基因；2)使用混合作图方法识别与非裔美国人(AA)金黄色葡萄球菌感染易感性相关的候选基因；3)通过外显子测序识别并优先考虑包含SAB的稀有、功能、编码序列变体的基因，特别是复杂的SAB；以及4)测试在原始R01中发现的现有候选基因与AIMS 1-3中新的候选基因在整个SABG队列中的相关性(1200例/1200对照)。该项目的长期目标是：1)确定金黄色葡萄球菌易感性的基因；2)调查这些基因在人类金黄色葡萄球菌菌血症中的临床重要性；以及3)最终使用这些基因来确定控制金黄色葡萄球菌感染的新干预措施。这笔赠款的成果将包括加强对金黄色葡萄球菌遗传易感性在决定感染的发展和严重程度方面的作用的了解。目前应用的全部价值还包括如果宿主基因和临床结果之间的联系对整个研究界的潜在好处(只有使用如此大量和特征良好的 来自受感染患者的DNA)可以被定义。这项工作对于加深对一个关键医学问题的理解至关重要，因为：1)金黄色葡萄球菌是一种新出现的病原体，2)减少金黄色葡萄球菌发病率的干预措施需要更好地了解感染的发展和严重程度的决定因素。了解这种疾病的宿主遗传决定因素将促进我们对葡萄球菌发病机制的理解，并将使保护公众健康免受这种病原体侵袭的关键进展成为可能。

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.