Cloning a major gene for mouse adenovirus susceptibility

描述（由申请人提供）：腺病毒导致5-10%的儿童呼吸道疾病，并与发展中国家儿童的急性肺炎有关，在那里它们是疾病和死亡的主要原因。5-15%的小儿骨髓移植患者发生腺病毒感染；发病率在50-80%之间。然而，关于腺病毒的发病机制，特别是宿主因素对疾病易感性的影响知之甚少。这些宿主因子的鉴定将有助于更好地设计抗病毒和免疫抑制疗法以及基于腺病毒的基因疗法。小鼠腺病毒1型（MAV-1）可以在自然宿主中进行研究，并且存在对MAV-1不同敏感性的近交系，为研究传染病的易感性提供了一个很好的模型。本提案的目的是定义和表征宿主基因(s)的一个主要的数量性状位点（QTL）的自交系小鼠mav1易感性。核心假设是，SJL/J小鼠15号染色体上与mav1易感性相关的主要QTL包含一个免疫系统基因，该基因在易感和耐药小鼠中都是多态性的。遗传作图将结合候选基因方法在两个特定的目标。(1)利用几种互补方法对主要的易感性QTL进行精细定位。高密度的多态性标记将用于重组后代回交、杂交和第三代杂交小鼠的基因型（重组后代测试）。我们将构建一个区间特异性基因株，将易感的SJL/J小鼠的区间基因导入到抗性的BALB/cJ背景中。将对其他近交系小鼠进行测试，以确定它们是否与SJL/J小鼠的主要QTL具有相同的易感性遗传基础。如果是这样，它们将用于精细定位、单倍型分析和候选基因鉴定。(2)筛选20 ~ 30个15号染色体QTL候选基因，比较易感菌株和耐药菌株之间的序列和基因表达差异。一个候选基因将被鉴定出来，并通过在抗性菌株中用易感等位基因替换它来进行遗传测试。该项目预计将确定以前未描述的宿主免疫反应和病毒免疫逃避之间的相互作用，从而增加我们对病毒感染和宿主对病原体反应机制的理解。

DESCRIPTION (provided by applicant): Adenoviruses cause 5-10% of respiratory illness in children and are associated with acute pneumonia in children in developing countries, where they are a major cause of illness and death. 5-15% of pediatric bone marrow transplant patients develop adenovirus infections; morbidity ranges from 50-80%. However, little is known about adenovirus pathogenesis, especially contributions of host factors to disease susceptibility. Identification of such host factors will enable better design of antiviral and immune suppressive therapy and adenovirus-based gene therapy. Mouse adenovirus type 1 (MAV-1) provides an excellent model for studying susceptibility to infectious disease, because it can be studied in the natural host and there are inbred strains with different susceptibilities to MAV-1. The objective of this proposal is to define and characterize the host gene(s) underlying a major quantitative trait locus (QTL) for MAV-1 susceptibility in inbred mice. The central hypothesis is that the major QTL on Chromosome 15 for MAV-1 susceptibility in SJL/J mice contains an immune system gene that is polymorphic in susceptible and resistant mice. Genetic mapping will be combined with candidate gene approaches in two specific aims. (1) The major QTL for susceptibility will be fine mapped using several complementary approaches. A high density of polymorphic markers will be used to genotype recombinant progeny backcross, intercross, and third-generation cross mice (recombinant progeny testing). An interval-specific congenic strain will be constructed in which the interval from susceptible SJL/J mice will be introgressed into the resistant BALB/cJ background. Additional inbred mouse strains will be tested to determine whether they share a genetic basis for susceptibility with the major QTL in SJL/J mice. If so they will be used for fine mapping, haplotype analysis, and candidate gene identification. (2) A list of 20-30 candidate genes for the Chromosome 15 QTL will be compared for sequence and gene expression differences between susceptible and resistant strains. A candidate gene will be identified and tested genetically by replacing it in a resistant strain with the susceptible allele. The project is expected to identify a previously undescribed interaction between host immune response and viral immune evasion, thus increasing our understanding of viral infections and mechanisms of host response to pathogens.