Genetic and mechanistic dissection of a lethal systemic virus infection

致命性全身病毒感染的遗传学和机制剖析

基本信息

批准号：
8872747
负责人：
JASON Kyle WHITMIRE
金额：
$ 19万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8872747
关键词：
Antibody Response Antiviral Agents Arenavirus Arenavirus Infections Bioinformatics Body Weight decreased Candidate Disease Gene Cells Cessation of life Characteristics Chromosomes, Human, Pair 11 Chromosomes, Human, Pair 9 Chronic Coupled DNA Sequence Alteration Data Disease Disease Outbreaks Disease Outcome Dissection Dominant Genetic Conditions Elements Employee Strikes Family Fever Gene Expression Genes Genetic Genetic Variation Genome Genomics Genotype Global Change Health Hematopoietic Immune response Immunoglobulins Individual Infection Inflammatory Inflammatory Response Inherited Lead Learning Lymphocytic choriomeningitis virus Maps Mediating Meiosis Molecular Morbidity - disease rate Mouse Strains Mus Mutation Outcome Partner in relationship Pathogenesis Phenotype Predisposition Production Quantitative Trait Loci Resolution Sequence Homology Shock Source Stretching Systemic infection T cell response T-Lymphocyte Therapeutic Time Tissues Transcript Variant Viral Viral Hemorrhagic Fevers Viral Pathogenesis Virus Virus Diseases Weight adaptive immunity base cytokine differential expression disorder risk forward genetics gain of function genetic element genetic variant immunopathology insight interest mortality prevent public health relevance response trait transcriptome sequencing

项目摘要

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.

描述（由适用提供）：全身病毒感染会引起明显的误差和死亡率，并且是全球范围内的重大健康问题。人们的疾病结局各不相同，这部分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和免疫球蛋白区域之外的基因组元素如何调节感染的致病结果。小鼠体育症病毒LCMV-CLONE13在感染后迅速传播，并在C57B6小鼠中导致有限的发病机理。我们已经确定了B6小鼠的基质，该基质在感染后发展出许多病毒性疾病热和全身性休克的特征，包括严重的体重减轻，过量的细胞因子产生以及组织损伤升高的证据。这两种菌株〜98％相同，但是我们已经确定了9号染色体上的30MB拉伸，并与严重的表型相关。引起基因座的疾病主要遗传在F1杂交中和100％渗透物中。我们假设严重的发病机理是由该区域中单个功能获得的基因引起的，该基因夸大了抗病毒T细胞反应。在这里，我们建议确定感染后导致严重发病机理的基因突变。 AIM1的目标是使用前遗传学，再加上生物信息学方法来缩小引起疾病的QTL以识别少量基因。我们将检查该间隔内的基因是否被差异表达，以及T细胞中是否存在全局基因表达变化。 AIM2的目标是确定是否需要用造血或非造血细胞表达引起疾病的基因型才能引起严重的发病机理。总体而言，该项目将确定在全身性染色体感染后导致严重发病机理的遗传局部。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敏感性的遗传因素。该信息对于识别病毒感染后患有疾病风险增加的个体和开发治疗以防止全身病毒感染后发生严重发病机理的人很有价值。