Platforms for synthesis and testing of emerging and zoonotic viruses

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There has been an increase in recognized trans-species movement and human disease from zoonotic viruses, as well as increased concern about intentional design and introduction of zoonotic organisms in bioterrorism. Our ability to respond to such emerging zoonotic-human viruses has been limited by our inability to predict the source, frequency, and mechanisms of virus host-species switching and adaptation. Recent advances in bioinformatics, molecular biology, structural biology, and synthetic biology, provide tools to design, synthetically reconstruct, and test new and emerging pathogens from sequence databases alone. However, development of broadly-applicable platforms strategies for emerging viruses has not occurred, in part due to concerns about possible misuse of synthetic biology and engineered host-range variants. We propose that is an essential mission of the RCEs to demonstrate the safe use and potential of synthetic biology in rapid response platforms. SARS-coronavirus (SARS-CoV) is a category C emerging pathogen that caused severe human disease worldwide. SARS-CoV is proposed to have emerged in humans following trans-species movement of Bat-Coronaviruses (Bat-CoV) that have been identified by sequence but have not been grown in culture. This proposal uses SARS-CoV and zoonotic Bat-CoV to establish platforms for recovery and testing of zoonotic viruses. The proposed program is comprised of four integrated Specific Aims that will design and synthetically reconstruct distinct serogroups of zoonotic bat-CoV from sequence databases, and define the determinants of host-species movement and adaptation in culture, and in young and senescent mouse models. Further, the Aims will develop strategies for stable and universal attenuation of pathogenesis of all coronavirus groups. The established approaches will allow rapid response and control of natural and deliberately designed human coronaviruses, and also will be directly applicable to development of similar specific rapid-response systems for recovery, analysis, attenuation and response to other category A, B, or C emerging pathogens of concern for human disease or bioterrorism.