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: 8234184
• 负责人: Mark R Denison
• 金额: $ 52.09万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234184
• 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.

公认的跨物种移动和人畜共患病的人类疾病有所增加 病毒，以及对故意设计和引入人畜共患生物体的日益关注 生物恐怖主义。我们应对此类新出现的人畜共患病毒的能力受到我们的限制。 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提供了工具 仅从序列数据库中设计、综合重建和测试新的和正在出现的病原体。 然而，针对新兴病毒的广泛适用的平台策略尚未开发出来。 部分原因是担心合成生物学和工程宿主范围变异可能被滥用。我们 提出 RCE 的一项基本任务是展示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 类新发病原体， 在全世界范围内引起了严重的人类疾病。 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-CoV 建立平台 人畜共患病病毒的回收和测试。拟议的计划由四个综合具体 目标是根据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，并定义文化和年轻人中宿主物种运动和适应的决定因素 和衰老小鼠模型。此外，目标将制定稳定和普遍衰减的策略 所有冠状病毒群的发病机制。既定方法将允许快速响应和控制 天然和精心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响应系统，用于恢复、分析、衰减和响应 其他 A、B 或 C 类新出现的引起人类疾病或生物恐怖主义的病原体。