Platforms for synthesis and testing of emerging and zoonotic viruses

从人畜共患病到公认的跨物种迁移和人类疾病的增加， 病毒，以及对故意设计和引进人畜共患病生物体的日益关注， 生物恐怖主义我们应对这种新出现的人畜共患病病毒的能力受到了我们的限制。 无法预测病毒宿主物种转换和适应的来源、频率和机制。 生物信息学、分子生物学、结构生物学和合成生物学的最新进展， 设计，综合重建，并测试新的和新兴的病原体从序列数据库单独。 然而，针对新兴病毒的广泛适用的平台策略的开发尚未发生， 部分原因是担心可能滥用合成生物学和工程宿主范围变体。我们 我建议，RCE的一项基本使命是证明合成药物的安全使用和潜力， 快速反应平台中的生物学。SARS冠状病毒（SARS-CoV）是一种C类新兴病原体， 在世界范围内引发了严重的人类疾病。SARS-CoV被认为是在人类中出现的， 蝙蝠冠状病毒（Bat-CoV）的跨物种移动，已通过序列鉴定，但 没有在文化中成长。该提案利用SARS-CoV和人畜共患蝙蝠冠状病毒建立平台， 人畜共患病病毒的回收和检测。该计划由四个具体的综合方案组成。 目的从序列设计和综合重建人畜共患蝙蝠冠状病毒的不同血清群 数据库，并定义了宿主种运动和适应文化的决定因素，并在年轻的 和衰老小鼠模型。此外，这些目标将制定稳定和普遍减毒的战略 所有冠状病毒组的发病机制。既定的方法将允许快速反应和控制 自然和故意设计的人类冠状病毒，也将直接适用于 开发类似的特定快速反应系统，用于回收、分析、衰减和应对 其他A、B或C类新出现的人类疾病或生物恐怖主义病原体。

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.