Human Genes Shaping the Response to Bio-Terrorism Agents

新出现的病原体具有被武器化为生物恐怖主义毒剂的独特潜力。 因为大多数人类对这种感染没有免疫力。人类对这些病原体的反应 从流产的感染到不堪重负的疾病和死亡。这种变化是由两个因素决定的 环境因素和宿主遗传因素(即易感等位基因)。我们在知识上的一个重大差距 这些遗传因素中的大多数是未知的。我们的目标是确定影响易感性的等位基因 使用候选基因方法的严重西尼罗河病毒(WNV)疾病。这样的等位基因必须在功能上 不同于野生型等位基因，因此可能受到自然选择的影响 可以从基因的变异模式中推断出来。因此，为了增加我们方法的力量，我们将 首先评估每个候选基因的变异模式，并使用这些数据来1)寻找功能等位基因，2) 确定哪些等位基因将在关联研究中最有用，以及3)确定影响 在西尼罗河病毒队列中对严重西尼罗河病毒病的易感性。为了权衡成功的几率对我们有利，我们将 分析已经在动物模型或体外发现的影响西尼罗河病毒疾病的基因。识别 与西尼罗河病毒病相关的等位基因将促进预后测试、疫苗和 治疗学；并提供关于如何找到其他新出现的病原体的易感等位基因的见解。 项目互动：该项目将与其他几个RCE项目和中心密切互动。西北风 病例查明将由莱尔·彼得森博士(CDC-DVBID)和富兰克林·贾德森博士(丹佛)协助 公共卫生)。Morrey博士(II.G.1)和Kedl博士(II.C.6)发现的影响小鼠WNV疾病的基因将 在人类西尼罗河病毒队列中进行研究，同样地，与人类西尼罗河病毒相关的变异的功能 疾病可以在Kedl博士开发的西尼罗河病毒小鼠模型中进行研究。我们的西尼罗河病毒队列 开发将为测试Corcoran博士开发的新诊断系统提供资源(二.1.1)。

Introduction: Emerging pathogens have a unique potential to be weaponized as bioterrorism agents because most humans have no immunity to such infections. The human response to these pathogens varies from aborted infection to overwhelming disease and death. This variation is determined by both environmental factors and host genetic factors (i.e. susceptibility alleles). A significant gap in our knowledge is that most of these genetic factors are unknown. Our goal is to identify alleles influencing susceptibility to severe West Nile virus (WNV) disease using a candidate gene approach. Such alleles must be functionally different than wild-type alleles, and thus likely to have been subject to natural selection¿the effects of which can be inferred from the pattern of variation in a gene. Thus, to increase the power of our approach we will first assess patterns of variation in each candidate gene and use these data to 1) find functional alleles, 2) determine which alleles will be most useful in association studies, and 3) identify alleles that influence susceptibility to severe WNV disease in a WNV cohort. To weight the odds of success in our favor, we will analyze genes that have been found in animal models or in vitro to influence WNV disease. Identifying alleles associated with WNV disease will facilitate the development of prognostic tests, vaccines, and therapeutics; and provide insights about how to find susceptibility alleles for other emerging pathogens. Project interactions: This project will closely interact with several other RCE projects and centers. WNV case ascertainment will be facilitated by Drs. Lyle Peterson (CDC-DVBID) and Franklyn Judson (Denver Public Health). Genes influencing murine WNV disease found by Drs. Morrey (II.G.1) and Kedl (II.C.6) will be studied in the human WNV cohort, and like-wise, the function of variants associated with human WNV disease can be studied in the WNV mouse model developed by Dr. Kedl (II.C.6). The WNV cohort we develop will provide a resource for testing new diagnostic systems developed by Dr. Corcoran (II.1.1).