Genetic Dissection of arenavirus-induced lethality

 描述（由申请人提供）： 出血热病毒引起严重的临床表现，病死率高，是严重的生物恐怖主义威胁。其中，拉沙病毒（LASV）是全球出血热的第二大常见原因，每年感染数十万人，每年导致约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。拉沙热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反应的差异如何影响血管完整性，以及对严重疾病易感性的遗传基础尚未确定。我们最近发现，淋巴细胞性脉络丛脑膜炎病毒（LCMV）变异体Cl13，被认为是LASV的模型，在NZB小鼠（但不是在B6小鼠）中引起严重的IFN依赖性血管渗漏，血小板丢失和死亡，出血热的主要特征。在另外的研究中，我们发现NZB和B6的F1杂交也是易感的，而F1xB6回交显示54%的死亡率，与孟德尔显性遗传的易感性模式兼容。该提案将1）使用来自受影响和未受影响的回交的DNA首次鉴定控制对沙粒病毒诱导的致死性的易感性的基因，以及2）通过在非易感B6小鼠中施加该突变来确认所鉴定基因的相关性。被鉴定的基因可能编码一种以前未被识别为病毒诱导的免疫和血管功能障碍的分子。因此，拟议的研究具有揭示拉沙和其他病毒性HF综合征治疗干预的新机制见解，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.