Host Susceptibility S. aureus

描述(由申请人提供)：这个项目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，而在那些有菌血症的人中，只有一些人会出现不良后果。在使用My K23创建了世界上最大的来自特征良好的金黄色葡萄球菌菌血症患者的DNA集合(n=400)后，我现在建议使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品系的小鼠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与金黄色葡萄球菌败血症易感性相关的基因清单。该项目的长期目标是：1)确定在小鼠模型中识别的基因内的多态是否与大量菌血症人群中金黄色葡萄球菌的易感性相关，以及2)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。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)在小鼠败血症模型中识别与金黄色葡萄球菌易感性相关的候选基因，在“敏感”和“耐药”近交系小鼠之间的电子作图和杂交中使用；2)优先选择候选基因并识别与金黄色葡萄球菌感染易感性相关的多态变异；以及3)测试这些多态变异在金黄色葡萄球菌菌血症患者中的重要性。这笔赠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能够被确定，那么未来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感染患者的DNA收集才有可能识别。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，并将使保护公众健康免受这种病原体感染的关键进展成为可能。

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.