Natural model for evaluating within- and cross-species virus transmission

项目摘要 全球病毒体极其多样化，新出现的病毒威胁全球健康。不幸的是，很少有感染 模型可以概括自然的传播和进化。在这里，我们建议在自然和实验之间架起桥梁 研究宿主内部和宿主之间的实时传播动态并推断病毒病原体的系统 两性关系。为了做到这一点，我们将利用一个模型，在这个模型中，宠物商店中的天然啮齿动物病原体 小鼠接触的是实验小鼠、大鼠、仓鼠或鹿鼠。该模型为研究提供了一个平台 病毒通过自然机制在宿主之间和宿主内的急性传播。这样做的一个主要优点是 模型是你可以接触到整个传输链，从储藏组织到脱落的东西，再到什么 在新主机中复制成功或失败。该提案的目标1将检验以下假设：持续时间 研究发现，干扰素的暴露和感染阶段是病毒在宿主体内传播和进化的形态。在这一目标中 我们将解决粪便、口腔和呼吸道传播问题。这项提案的目标2将检验以下假设 进化距离和干扰素决定了跨物种传播事件的成功。致信地址 我们将使用wt和STAT2缺陷的大鼠、仓鼠和鹿小鼠。重要的是，这项提议将产生 STAT2缺陷大鼠。目前，尚不存在先天免疫缺陷大鼠，这项提议将提供 这是该领域无价的工具。我们将测量天然老鼠病毒跨越物种屏障的能力。 并确定进化距离和先天抗病毒反应的影响。总体而言，这项提议将 开发和开发一个模型系统，允许分析天然啮齿动物病毒传播到 描述人畜共患病的生物学障碍。

Project Summary The global virome is incredibly diverse and emerging viruses threaten global health. Unfortunately, few infection models can recapitulate natural transmission and evolution. Here we propose to bridge natural and experimental systems to study real-time transmission dynamics within and between hosts and infer virus-pathogen relationships. To accomplish this we will leverage a model whereby the natural rodent pathogens from pet store mice are exposed to laboratory mice, rats, hamsters, or deer mice. This model offers a platform for studying acute transmission of viruses between and within hosts via natural mechanisms. One major advantage of this model is that you can access the entire transmission chain from the reservoir tissue, to what is shed, to what either succeeds or fails to replicate in the new host. Aim 1 of this proposal will test the hypothesis that the duration of exposure, interferon and stage of infection in the reservoir shape virus transmission and evolution. In this aim we will address fecal oral and respiratory transmission. Aim 2 of this proposal will test the hypothesis that evolutionary distance and interferon determine the success of cross-species transmission events. To address this we will use wt and STAT2 deficient rats, hamsters, and deer mice. Importantly, this proposal will generate STAT2 deficient rats. Currently, there are no innate immune deficient rats exists and this proposal will provide an invaluable tool for the field. We will measure the capacity of natural mouse viruses to cross the species barrier and determine the impact of evolutionary distance and innate antiviral responses. Overall, this proposal will develop and exploit a model system allows for the analysis of transmission of natural rodent viruses to characterize biological barriers to zoonosis.