Variation in Human Innate Immunity

该项目的重点是确定决定人类对生物武器的易感性的因素。 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。来自人类和动物研究的证据支持这一概念 因素，其中一些是由基因决定的，是疾病易感性的重要修饰因素。 例如疟疾和脑膜炎双球菌感染。有相当多的证据表明有人 细菌产物的先天免疫炎性反应的个体变异性。这种可变性是 可能延伸到对细菌产物的先天免疫性炎症反应，这些细菌产物可能被用作 生物武器制剂，并可能影响接触此类制剂后的结果。一种对 人类先天免疫炎性反应变异的分子机制 这些药物可能有助于前瞻性地识别高危人群的不良结局 生化武器攻击。这将有助于优化资源分配，并可能确定新的 治疗靶点。我们建议测量对鼠疫和鼠疫的先天免疫反应的变异性。 使用全血对细菌反应的体外模型的其他潜在的生物武器制剂 产品。我们将研究这种变异的遗传成分的大小，通过一个 经典双胞胎研究。我们将确定特定等位基因单倍型对 这种可变性。最后，我们将确定慢性阻塞性肺疾病患者的先天免疫反应特征。 呼吸道疾病，这是一个很可能在发生以下情况时预后不良的高风险人群 暴露于雾化鼠疫杆菌和其他生物武器制剂。我们最初的重点将放在Y。 但在这些研究中开发的方法将适用于其他 潜在的生化武器制剂。

This project focuses on identifying the factors that determine 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. Evidence from human and animal studies supports the concept that host factors, some of which are genetically determined, are important modifiers of susceptibility to diseases such as malaria and meningococcal infection. There is considerable evidence demonstrating person to person variability in innate immune inflammatory responses to bacterial products. This variability is likely to extend to innate immune inflammatory responses to products of bacteria that may be used as bioweapons agents and could influence outcomes after exposure to such agents. An understanding of the molecular mechanisms underlying human variability in innate immune inflammatory responses to these agents may help to prospectively identify populations at high-risk for poor outcomes after a bioweapons attack. This would aid in the optimal allocation of resources and may identify new therapeutic targets. We propose to measure the variability in innate immune responses to Y. pestis and other potential bioweapons agents using an in vitro model of whole blood responses to bacterial products. We will investigate the magnitude of the genetic component of this variability through a classical twins study. We will determine the extent to which specific allelic haplotypes contribute to this variability. Finally, we will identify innate immune response profiles in patients with chronic respiratory diseases, a population that is likely to be at high-risk for poor outcomes in the event of exposure to aerosolized Y. pestis and other bioweapons agents. Our initial emphasis will be on Y. pestis, but the approaches developed in these studies will be adapted to subsequent studies of other potential bioweapons agents.