Genetic and mechanistic dissection of a lethal systemic virus infection

 描述(申请人提供)：系统性病毒感染导致严重的发病率和死亡率，是一个重大的世界性健康问题。人们的疾病结局各不相同，这在一定程度上是由于整个基因组中的自然等位基因变异。我们有兴趣更好地了解MHC、TCR和免疫球蛋白区域以外的基因组元件如何调节感染的致病结果。鼠源病毒LCMV-clone13一旦感染就会迅速传播，并在C57B6小鼠中引起有限的致病作用。我们已经确定了B6小鼠的一个亚系，它在感染后发展为病毒性出血热和系统性休克的许多特征，包括严重的体重减轻，过量的细胞因子产生，以及组织损伤增加的证据。这两个菌株约98%相同，但我们在9号染色体上发现了一个30Mb的延伸，这与严重的表型有关。致病基因座在F1组合中以显性遗传为主，为100%透性。我们假设，严重的发病机制是由该区域的一个单一的功能获得基因引起的，该基因夸大了抗病毒T细胞反应。在这里，我们建议确定导致感染后严重发病机制的基因突变。Aim1的目标是使用正向遗传学和生物信息学相结合的方法来缩小致病QTL的范围，以识别少量基因。我们将检查这一区间内的基因是否存在差异表达，以及T细胞中是否存在整体基因表达的变化。AIM2的目的是确定致病基因是否需要由造血细胞或非造血细胞表达才能导致严重的发病。总体而言，该项目将确定在系统性病毒感染后导致严重发病的遗传位点。这些努力将支持一项长期努力，以识别和表征增加对病毒感染易感性的遗传因素。这些信息对于识别病毒感染后疾病风险增加的个体以及开发预防系统性病毒感染后严重发病机制的治疗方法都是有价值的。

 DESCRIPTION (provided by applicant): Systemic virus infections cause significant morbitity and mortality and are a significant worldwide health problem. People vary in disease outcome, and this is partly due to natural allelic variation throughout the genome. We are interested in better understanding how genomic elements outside of the MHC, TCR, and immunoglobulin regions regulate pathogenic outcomes to infection. The mouse arenavirus, LCMV-clone13, rapidly disseminates upon infection and causes limited pathogenesis in C57B6 mice. We have identified a substrain of B6 mouse that develops many characteristics of viral hemmoragic fever and systemic shock following infection, including severe weight loss, excessive cytokine production, and evidence of elevated tissue damage. These two strains are ~98% identical, but we have identified a 30Mb stretch on Chromosome 9 that and associates with the severe phenotype. The disease causing locus is dominantly inherited in F1 crosses and 100% penetrant. We hypothesize that the severe pathogenesis is caused by a single, gain-of-function gene in this region that exaggerates the antiviral T cell response. Here, we propose to identify the genetic mutation that causes severe pathogenesis after infection. The objectives of Aim1 are to use forward genetics coupled with bioinformatic approaches to narrow the disease-causing QTL to identify a small number of genes. We will examine whether genes within this interval are differentially expressed and whether there are global gene expression changes in T cells. The objectives of Aim2 are to determine whether the disease-causing genotype needs to be expressed by hematopoietic or non- hematopoietic cells to cause severe pathogenesis. Overall, this project will identify genetic loci that cause severe pathogenesis after systemic viru infection. These efforts will support a long-term endeavor to identify and characterize genetic elements that increase susceptibility to virus infection. This information is valuable for identifyng individuals at increased risk of disease after virus infection and for developing therapeutics to prevent severe pathogenesis following systemic virus infection.