Platforms for synthesis and testing of emerging and zoonotic viruses

已知的跨物种迁徙和人畜共患疾病有所增加。 病毒，以及对故意设计和引入人畜共患病生物的日益关注 生物恐怖主义。我们对这种新出现的人畜共患病毒的反应能力受到我们的 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为 仅从序列数据库设计、综合重建和测试新出现的病原体。 然而，针对新出现的病毒的广泛适用的平台策略的开发尚未发生， 部分原因是担心合成生物学和工程寄主范围变体可能被滥用。我们 建议RCES的一项基本任务是证明合成材料的安全使用和潜力 快速反应平台中的生物学。SARS冠状病毒(SARS-CoV)是一种新出现的C类病原体 在世界范围内引发了严重的人类疾病。SARS冠状病毒被认为是在以下情况下在人类中出现的 已通过序列鉴定的蝙蝠冠状病毒(BAT-CoV)的跨物种移动 不是在培养中培养出来的。该方案利用SARS冠状病毒和人畜共患蝙蝠冠状病毒建立平台，为 人畜共患病毒的恢复和检测。拟议的计划由四个综合的具体方案组成 旨在从序列中设计和综合重建不同的人兽共患蝙蝠冠状病毒血清群 数据库，并确定寄主物种在文化和幼体中移动和适应的决定因素 和衰老的小鼠模型。此外，AIMS将制定稳定和普遍衰减的战略 所有冠状病毒组的致病机制。已建立的方法将允许快速反应和控制 自然和精心设计的人类冠状病毒，也将直接适用于 开发用于恢复、分析、衰减和应对的类似的特定快速反应系统 其他与人类疾病或生物恐怖主义有关的新出现的A、B或C类病原体。

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.