A genetic systems approach to host-pathogen interaction in orthopoxvir infections

正痘病毒、天花病毒、鼠痘病毒和猴痘病毒在较小程度上具有狭窄的 宿主范围，但对于其他病毒（牛痘和牛痘病毒），宿主范围要广泛得多。鉴于 生物恐怖主义的关注和病毒如何“跳跃”到新的宿主物种的问题（这两个主要关注的问题， SERCEB），研究和鉴定决定和调节宿主范围的宿主基因网络是必要的。 然而，对决定允许、限制或临床病程的宿主基因知之甚少。 疾病为了阐明这些宿主基因，我们将筛选一组遗传多样性的C57 BL/6 J和DBA/2 J， 高级重组近交系（BXD ARI）小鼠对从牛痘开始的感染的易感性， 鼠痘病毒建立系统，其后是猴痘病毒。这些鼠标和相关服务 由SAID Core E提供。特定病毒的相对宽容性，再加上遗传因素， 对受感染动物与未受感染动物的特征分析和高级生物信息学分析 （genenetwork.org）将确定对耐药性/易感性至关重要的特定宿主基因/途径。 感染，使我们更好地了解宿主和病原体之间的关系。这些 研究结果将为设计新的干预策略、抗病毒治疗的新靶点 并为“物种跳跃”如何发生提供线索，并确定宿主生物标志物的组合 可用于预后目的的易感性/耐药基因，以及筛选 其他病原体。我们提出以下具体目标：具体目标1： 宿主基因型的哪种变异调节了鼠痘、牛痘和猴痘的感染表型 病毒将在亲代和BXD小鼠中标准化感染条件并评价疾病;特异性 目的2：我们将定位数量性状基因座（QTL），定义相关的已知和新的候选基因网络， 可能导致疾病严重程度的基因和途径。具体目标3：我们建议 确认和利用相关基因/途径以开发抗病毒药物和干预措施的策略 战略

The orthopoxviruses, smallpox (variola), ectromelia and to a lesser extent monkeypox virus have narrow host ranges but for others (vaccinia and cowpox viruses) the host range is much more extensive. In light of bioterrorism concerns and the question of how viruses "jump" into new host species (both major concerns of SERCEB), it is imperative to study and identify host gene networks that determine and regulate host range. However, little is known about host genes that determine permissiveness, restriction or clinical course of disease. To elucidate such host genes, we will screen a panel of genetically diverse, C57BL/6J and DBA/2J advanced recombinant inbred (BXD ARI) mice for susceptibility to infection beginning with cowpox and ectromelia virus to establish the system and thereafter monkeypox virus. These mice and relevant services are provided by the SAID Core E. The relative permissiveness of a given virus, coupled with the genetic profiling of the infected versus the uninfected animals and an advanced bioinformatic analysis (genenetwork.org) will identify specific host genes/pathways which are critical for resistance/susceptibility of the infections and provide us a better understanding of the relationship between host and pathogen. These results will provide insight into the design of new intervention strategies, new targets for antiviral therapies and provide clues as to how "species jumping" might occur and identify combinations of biomarkers of host susceptibility/resistance genes that can be used for prognostic purposes and a platform for the screening of other pathogens. We propose the following specific aims: Specific Aim 1: We will determine the extent by which variation in host genotype modulates the infection phenotype of Ectromelia, Cowpox and Monkeypox viruses. Infection conditions will be standardized and disease evaluated in parental and BXD mice; Specific Aim 2: We will map quantitative trait loci (QTL), define relevant known and novel networks of candidate genes and pathways that are likely to contribute to disease severity and. Specific Aim 3: We propose strategies to confirm and exploit the implicated genes/pathways to develop antivirals and intervention strategies