Genetic Dissection of arenavirus-induced lethality

 描述(由申请人提供)： 出血热病毒临床表现严重，病死率高，是严重的生物恐怖主义威胁。其中，拉萨病毒(LASV)是全球第二大最常见的出血热病因，每年感染数十万人，最终导致每年约5,000至20,000人死亡。目前还没有批准的疫苗，治疗选择也有限。LASA和其他出血热的主要特征是内皮损伤、血小板丢失和血管渗漏，严重时会导致组织水肿、器官衰竭和死亡。然而，免疫和内皮细胞对LASV的反应差异如何可能影响血管完整性，以及严重疾病易感性的遗传基础还没有确定。我们最近发现，淋巴细胞性脉络膜脑膜炎病毒(LCMV)变异株Cl13被认为是LASV的模型，在NZB小鼠(但在B6小鼠中不是)引起严重的干扰素依赖性血管渗漏、血小板丢失和死亡，这是出血热的主要特征。在进一步的研究中，我们发现NZB和B6的F1组合也是感病的，而F1xB6回交表现出54%的死亡率，这一模式符合孟德尔的感病显性遗传。这项建议将1)使用受影响和未受影响的回交的DNA来首次识别控制ArenaVirus诱导的致死性的易感性的基因，以及2)通过在不敏感的B6小鼠身上施加这种突变来确认所识别的基因的相关性。已识别的基因可能编码一种分子，以前没有被认为是病毒诱导的免疫和血管功能障碍的贡献者。因此，这项拟议的研究具有揭示LASA和其他病毒性心力衰竭综合征治疗干预的新的机制、遗传基础和分子靶点的潜力。

 DESCRIPTION (provided by applicant): Hemorrhagic fever viruses cause severe clinical manifestations with high case fatality rates and are serious bioterrorism threats. Among them, Lassa virus (LASV) is the second most common cause of hemorrhagic fevers worldwide, infects hundreds of thousands of individuals annually, culminating in ~5,000 to 20,000 deaths per year. There is no approved vaccine and treatment options are limited. The main characteristics of Lassa and other hemorrhagic fevers are endothelial damage, platelet loss and vascular leakage, leading to tissue edema, organ failure and death in severe cases. However, how differences in immune and endothelial cell responses to LASV might affect vascular integrity, and the genetic basis for susceptibility to severe disease, have not been defined. We recently showed that the lymphocytic choriomeningitis virus (LCMV) variant Cl13, considered a model of LASV, causes in NZB mice (but not in B6 mice) severe IFN-dependent vascular leakage, platelet loss, and death, the main characteristics of hemorrhagic fevers. In additional studies we showed that F1 crosses of NZB and B6 are also susceptible, while F1xB6 backcrosses showed 54% mortality, a pattern compatible with Mendelian dominant inheritance of susceptibility. This proposal will 1) use DNA from affected and non-affected backcrosses to identify for the first time a gene that controls susceptibility to arenavirus-induced lethality, and 2) confirm the relevance of the identified gene by imposing this mutation in non-susceptible B6 mice. The identified gene might encode a molecule previously unrecognized as being a contributor to virus-induced immune and vascular dysfunctions. Thus, the proposed study holds the potential of revealing new mechanistic insights, genetic basis, and molecular targets of therapeutic intervention for Lassa and other viral HF syndromes.