Human Innate Immune Variation

该项目的重点是确定可能改变人类对生物武器敏感性的因素 剂.这是一个重要的目标，因为我们需要能够确定高风险群体，以便针对 有效的预防措施。迄今为止，我们的工作取得了几项重要发现：1） 在人类先天免疫应答中存在高度的个体间差异， 一系列先天免疫激动剂，2）确定这种个体间变异的大部分是 由于遗传因素，3）Toll样蛋白基因内许多常见遗传变异的鉴定 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TLR 1基因中鉴定出一种高功能的遗传变异体， 改变TLR 1介导的反应并预测脓毒症患者的器官功能障碍和死亡， 败血性休克本次更新中提出的研究将继续解决主要假设： 对潜在生物武器如Y. 鼠疫是由特定的遗传变异改变的，这影响了宿主对感染的易感性。 在前一个资助期内，我们招募了先天性免疫反应并对其进行了表征。 我们还收集了800多名健康志愿者的基因组DNA， 样品除了拟议的核心资源外，我们还将利用这一独特的资源，作为该RCEB的一部分 应用，以进一步了解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TLR 4、TLR 7/8和NOD 2激动剂的非常高或非常低的全血细胞因子应答， vivo.在目的2中，我们将确定TLR通路相关基因的遗传多态性对TLR通路的影响。 单核细胞和肺泡巨噬细胞对体外选定药物感染的反应。最后，在Aim 3中 我们将确定人类TLR 1多态性在体内感染鼠疫菌和土拉热杆菌中的作用 对小鼠通过这些拟议的研究将获得重要的新见解的遗传控制的先天 对来自重要选择因子的细菌产物的免疫应答以及这些遗传控制因子如何 反应影响宿主对活病原体的体外和体内反应。

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.