Platforms for synthesis and testing of emerging and zoonotic viruses

新兴病毒和人畜共患病毒的合成和测试平台

• 批准号: 8375872
• 负责人: Mark R Denison
• 金额: $ 54.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8375872
• 关键词: Animals; Attenuated; Bioinformatics; Biological Models; Bioterrorism; Categories; Chiroptera; Clinical; Computer Simulation; Coronavirus; Cultured Cells; Databases; Deletion Mutation; Development; Distant; Engineering; Epidemic; Epithelial Cells; Ferrets; Frequencies; Future; Genetic Transcription; Genome; Goals; Growth; Human; Human Virus; In Vitro; Interferons; Intervention; Kinetics; Maps; Mission; Modeling; Molecular Biology; Movement; Mus; Mutation; Organism; Pathogenesis; Pharmaceutical Preparations; Phenotype; Phylogenetic Analysis; Polyproteins; Proteins; Public Health; Recombinants; Recovery; Role; SARS coronavirus; Source; Subgroup; System; Testing; Transgenic Mice; Vaccines; Variant; Viral; Virulence; Virus; Virus Receptors; Viverridae; aged; attenuation; biodefense; coronavirus spike glycoprotein; design; engineering design; human coronavirus; human disease; in vivo; mouse model; novel virus; pandemic disease; pathogen; prevent; programs; receptor; recombinational repair; reconstruction; replicase; response; senescence; structural biology; synthetic biology; tool; transmission process

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.

人畜共患病的公认的跨物种运动和人类疾病有所增加 病毒，以及对人畜共患生物的故意设计和引入的越来越关注 生物恐怖。我们对这种新兴人畜共患病毒的反应能力受到我们的限制 无法预测病毒宿主特征切换和适应的来源，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提供了工具 设计，合成重建和从序列数据库中测试新的和新兴的病原体。 但是，开发针对新兴病毒的广泛应用平台策略尚未发生 部分原因是担心可能滥用合成生物学和工程宿主范围的变体。我们 提出这是RCE的重要任务，以证明合成的安全使用和潜力 快速响应平台中的生物学。 SARS-CORONAVIRUS（SARS-COV）是一种类别C的新兴病原体 在全球引起严重的人类疾病。建议SARS-COV在人类中出现 通过序列鉴定但具有的蝙蝠病毒（BAT-COV）的反式物种运动 没有在文化中种植。该提案使用SARS-COV和人畜共努性Bat-CoV来建立平台 人畜共患病毒的恢复和测试。提出的程序由四个集成的特定特定组成 将设计和合成从序列设计和合成的人畜共患的血清群 数据库，并定义培养物中宿主物种运动和适应的决定因素，以及年轻人 和衰老的小鼠模型。此外，目标将制定稳定和普遍衰减的策略 所有冠状病毒组的发病机理。既定方法将允许快速响应和控制 天然和故意设计的人类冠状病毒，也将直接适用于 开发相似的特定快速响应系统，用于恢复，分析，衰减和对 其他对人类疾病或生物恐怖主义关注的A类，B或C类新的病原体。