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.