Variation in Human Innate Immunity

这个项目的重点是确定决定人类对生物武器易感性的因素 剂.这是一个重要的目标，因为我们需要能够识别高风险群体，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宿主 某些因素是由遗传决定的，它们是疾病易感性的重要调节因素 如疟疾和脑膜炎球菌感染。有相当多的证据表明， 人对细菌产物的先天免疫炎症反应的差异性。这种可变性是 可能延伸到先天免疫炎症反应的产品的细菌，可用于 生物武器制剂，并可能影响接触这些制剂后的结果。了解 先天免疫炎症反应中人类变异性的分子机制， 这些药物可能有助于前瞻性地识别在治疗后不良结局的高风险人群。 生化武器袭击这将有助于资源的最佳分配，并可能发现新的 治疗目标我们建议测量先天免疫反应的变异性Y。菌与 使用全血对细菌应答的体外模型 产品.我们将通过一项研究来调查这种变异性的遗传成分的大小。 经典双胞胎研究我们将确定特定等位基因单倍型在多大程度上有助于 这种可变性。最后，我们将确定慢性乙型肝炎患者的先天免疫反应概况， 呼吸道疾病，这是一个很可能是在高风险的情况下，结果不佳的人口 暴露于雾化的Y。鼠疫和其他生物武器我们最初的重点将放在Y上。 鼠疫，但在这些研究中开发的方法将适用于其他后续研究 潜在的生化武器

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.