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

项目摘要 全球病毒组的多样性令人难以置信，新出现的病毒威胁着全球健康。不幸的是，很少有感染 模型可以概括自然传播和进化。在这里，我们建议桥接自然和实验 研究宿主内和宿主间实时传播动态并推断病毒-病原体的系统 关系。为了实现这一目标，我们将利用一个模型，其中来自宠物店的天然啮齿动物病原体 将小鼠暴露于实验室小鼠、大鼠、仓鼠或鹿鼠。该模型提供了一个研究 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 你可以接触到整个传播链，从储存组织到脱落的组织， 在新主机中复制成功或失败。本提案的目标1将测试持续时间的假设 暴露量、干扰素和感染阶段在水库形状病毒传播和演变。在这一目标中， 我们将解决粪便、口腔和呼吸道传播问题。本提案的目标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。解决 我们将使用WT和STAT 2缺陷的大鼠、仓鼠和鹿鼠。重要的是，这项提案将产生 STAT 2缺陷大鼠。目前，没有先天性免疫缺陷大鼠存在，这一建议将提供 这是一个非常宝贵的工具。我们将测量自然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。总的来说，这项建议将 开发和利用一个模型系统，可以分析自然啮齿动物病毒的传播， 描述人畜共患病的生物屏障。

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.