Human Innate Immune Variation

该项目的重点是确定可能改变人类对生化武器易感性的因素。 探员们。这是一个重要的目标，因为我们需要能够识别高危群体，以便针对 有效的预防措施。到目前为止，我们的工作已经产生了几个重要的发现：1) 存在高度个体间差异的人类先天免疫反应的多样性 先天免疫激动剂的范围，2)决定了这种个体间变异的很大比例是 由于遗传因素，3)确定了许多常见的遗传变异的基因内的托尔样 受体(TLR)反应途径与测量的先天免疫反应高度相关 在体外，4)在TLR1基因中鉴定出一个高功能的遗传变异，该变异显著地 脓毒症患者TLR1介导的反应改变并预测器官功能障碍和死亡 感染性休克。本次更新中提出的研究将继续解决基本假设： 对潜在生物武器制剂的先天免疫反应的个体间差异。 鼠疫病毒被特定的遗传变异所修饰，这些变异影响宿主对感染的易感性。 在之前的资助期中，我们已经登记并表征了先天免疫反应。 给800多名健康志愿者的一大批激动剂，我们也为他们收集了基因组DNA 样本。除了建议的核心资源外，我们还将利用这一独特的资源作为RCEB的一部分 应用来加深我们对遗传因素如何改变人类宿主对 感染。在目标1中，我们将进行全基因组关联研究，以确定新的遗传因素。 预测对TLR4、TLR7/8和NOD2激动剂EX的全血细胞因子应答很高或很低 活着。在目标2中，我们将确定TLR途径相关基因的遗传多态对TLR信号转导的影响。 体外单核细胞和肺泡巨噬细胞对选择性药物感染的反应。最后，在目标3中 我们将在活体内确定人类TLR1基因多态性在鼠疫杆菌和图拉氏杆菌感染中的作用 在老鼠身上。通过这些拟议的研究，将获得对先天遗传控制的重要新见解 对来自重要选择制剂的细菌产品的免疫反应以及这些免疫反应是如何由基因控制的 在体外和体内，反应影响宿主对活体病原体的反应。

This project is focused on the identification of factors that could alter human susceptibility to bioweapons agents. This is an important goal, as we need to be able to identify high-risk groups in order to target effective preventive measures. Our work to date has resulted in several important findings: 1) the existence of a high degree of inter-individual variation in human innate immune responses to a diverse range of innate immune agonists, 2) determined that a large proportion of this inter-individual variation is due to heritable factors, 3) the identification of numerous common genetic variants within genes of the tolllike receptor (TLR) response pathway that are highly associated with innate immune responses measured in vitro, 4) the identification of a highly functional genetic variant in the gene for TLR1 that dramatically alters TLR1-mediated responses and predicts organ dysfunction and death in patients with sepsis and septic shock. The studies proposed in this renewal will continue to address the Primary Hypothesis: Inter-individual variability in innate immune responses to potential bioweapons agents such as Y. pestis is modified by specific genetic variants, which influence host susceptibility to infection. Over the course of the prior funding period we have enrolled and characterized innate immune responses to a large panel of agonists in over 800 healthy volunteers for whom we have also collected genomic DNA samples. We will employ this unique resource in addition to proposed core resources as part of this RCEB application to further our understanding of how genetic factors modify human host susceptibility to infection. In Aim 1 we will perform a genome-wide association study to identify novel genetic factors predicting very high or very low whole blood cytokine responses to TLR4, TLR7/8, and NOD2 agonists ex vivo. In Aim 2 we will determine the effect of genetic polymorphisms in TLR pathway-related genes on the response of monocytes and alveolar macrophages to infection with select agents in vitro. Finally, in Aim 3 we will determine the role of human TLR1 polymorphisms on infection with Y.pestis and F.tularensis in vivo in mice. Through these proposed studies will gain important new insights into the genetic control of innate immune responses to bacterial products from important select agents and how these genetically controlled responses affect host responses to live pathogens in vitro and in vivo.