Host Susceptibility S. aureus

描述（由申请人提供）：该项目的总体目标是进一步了解为什么有些人会发生金黄色葡萄球菌感染，而在菌血症患者中，只有一些人会发生不良后果。利用我的K23建立了世界上最大的金黄色葡萄球菌菌血症患者DNA集合（n=400），我现在建议利用这一现有资源来评估宿主对金黄色葡萄球菌易感性的遗传决定因素。我们观察到，遗传上不同的小鼠菌株对金黄色葡萄球菌表现出不同的全身反应，并在小鼠模型中确定了一系列与金黄色葡萄球菌脓毒症易感性相关的基因。该项目的长期目标是：1)确定小鼠模型中鉴定的基因多态性是否与大量菌血症患者对金黄色葡萄球菌的易感性相关，2)最终使用这些基因确定控制金黄色葡萄球菌感染的新干预措施。在本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风险和严重程度的重要决定因素。为了验证这一假设，我们建议：1)在小鼠脓毒症模型中，利用计算机定位和“敏感”和“耐药”小鼠菌株之间的交叉杂交，确定与金黄色葡萄球菌易感性相关的候选基因；2)筛选候选基因，鉴定金黄色葡萄球菌感染易感性相关的多态性变异；3)检测这些多态性变异在金黄色葡萄球菌菌血症患者中的重要性。这笔拨款的成果将包括增加对金黄色葡萄球菌遗传易感性在确定感染严重程度方面的作用的理解。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关联能够被确定，那么整个研究界的潜在未来利益，只有使用来自感染患者的如此大量且特征明确的DNA收集才能确定。这项工作对于进一步了解一个关键的医学问题至关重要，因为：1)金黄色葡萄球菌是一种新兴的病原体，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严重程度的决定因素。了解金黄色葡萄球菌感染中疾病严重程度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，并将在保护公众健康免受这种病原体侵害方面取得关键进展。

DESCRIPTION (provided by applicant): The overall goal of this project is to further understand why some individuals develop Staphylococcus aureus infection, and of those with bacteremia, only some develop adverse outcomes. Having used my K23 to create the world's largest collection of DNA from well-characterized patients with S. aureus bacteremia (n=400), I now propose to use this existing resource to evaluate genetic determinants of host susceptibility to S. aureus. We have observed that genetically distinct strains of mice exhibit a variable systemic response to S. aureus, and have identified a list of genes associated with susceptibility to S. aureus sepsis in the mouse model. The long-term objectives of this project are to: 1) determine whether polymorphisms within the genes identified in the mouse model are associated with susceptibility to S. aureus in a large cohort of humans with bacteremia, and 2) ultimately use these genes to identify novel interventions for the control of S. aureus infections. The specific hypothesis to be tested in this application is that identifiable host genetic factors are important determinants of risk for and severity of S. aureus infection. In order to test this hypothesis, we propose to: 1) Identify candidate genes associated with susceptibility to S. aureus in a murine sepsis model, using both in silico mapping and intercrosses between "sensitive" and "resistant" strains of inbred mice; 2) Prioritize candidate genes and identify polymorphic variants associated with susceptibility to S. aureus infection; and 3) Test the importance of these polymorphic variants in patients with S. aureus bacteremia. The products of this grant will include an increased understanding of the role of genetic susceptibility to S. aureus in determining the severity of infection. The full value of the current application also includes the potential future benefit to the research community as a whole if associations 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 severity of infection. Understanding the host genetic determinants of disease severity in S. aureus infections will advance our understanding of staphylococcal pathogenesis and will enable key advances in protecting the public health from this pathogen.