Diversity of Host Pathogen Interactions

尽管公共卫生有所改善，疫苗的进步，以及许多类别的 抗生素、传染病仍占全球所有死亡人数的四分之一以上。然而，即使是 对于最具破坏性的大流行，历史表明，在严重程度和持续时间上存在很大差异 感染。尽管如此，人类多态与易感性之间的联系的例子很少。 细菌是已知的。 这个项目的目标是：1)确定人类细菌感染的哪些方面是可遗传的 变异，2)确定导致的遗传变化，以及3)评估这一变化的相关性 整个生物体适合度的变化。我们正在测量易感性的中间表型 使用从明显正常的个体群体中提取的细胞。细菌摄取、复制、 定位，宿主细胞存活和细胞因子的产生提供了一幅定量的细胞图像 感染。基于家庭的关联分析被用来将这些化验的值与 基于相关细胞微生物学和全基因组范围选择的候选基因中的SNPs。 已确定的SNPs的原因是通过结合表达分析、RNA 干扰和过度表达实验。最后，将衡量与健康和疾病的相关性 对转基因小鼠的临床表型和表型测量进行关联分析。

Despite improvements in public health, advancements in vaccines, and the development of many classes of antibiotics, infectious disease is still responsible for over a quarter of all deaths worldwide. However, even for the most devastating of pandemics, history demonstrates a large variability in the severity and duration of infection. Despite this, few examples of association between human polymorphism and susceptibility to bacteria are known. The goals of this project are to 1) identify aspects of bacterial infection in humans that exhibit heritable variation, 2) determine the genetic changes that are responsible, and 3) assess the relevance of this variation on the fitness of whole organisms. We are measuring intermediate phenotypes of susceptibility using cells derived from populations of apparently normal individuals. Assays of bacterial uptake, replication, and localization, and host-cell survival and cytokine production provide a quantitative, cellular picture of infection. Family-based association analyses are being used to correlate values from these assays with SNPs in candidate genes selected based on relevant cellular microbiology and on a genome-wide scale. Causation of the identified SNPs is being established by a combination of expression analysis, RNA interference, and overexpression experiments. Finally, relevance to health and disease will be measured using association analysis of clinical phenotypes and phenotypic measurements of transgenic mice.