US-UK Collab: Modelling reassortment at the cellular, clinical, and phylogenetic level in emerging Bunyaviruses

美英合作：在新兴布尼亚病毒的细胞、临床和系统发育水平上模拟重配

基本信息

批准号：
10379508
负责人：
Carmen Molina-Paris
金额：
$ 45.57万
依托单位：
TRIAD NATIONAL SECURITY, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10379508
关键词：
Address Affect Arthropods Bunyaviridae Cells Clinical Crimean Hemorrhagic Fever Crimean-Congo Hemorrhagic Fever Virus Data Data Collection Data Set Disease Disease Outbreaks Ecology Ensure Epidemic Epidemiology Evolution Family Frequencies Gene Expression Genes Genetic Enhancement Genetic Recombination Genome Genotype Health Human In Vitro Infection Influenza A virus Joints Life Cycle Stages Meleagris gallopavo Mentors Methods Modeling Orthobunyavirus Other Genetics Phylogenetic Analysis Phylogeny Play Point Mutation Population Postdoctoral Fellow Prevention approach Process Protocols documentation Public Health RNA Recording of previous events Research Research Personnel Risk Role Sampling Standardization Tajikistan Ticks Time Vertebrates Viral Genes Virion Virus Virus Replication Work biobank improved laboratory experiment mathematical model novel novel virus pandemic disease public health emergency research and development transmission process vector viral transmission

项目摘要

Genome segmentation has important implications for viral gene expression control and RNA assembly into nascent virions. It also creates the potential for reassortment: the exchange of intact gene segments between viruses that coinfect the same cell. Reassortment is different from recombination since it allows many distinct genotypes to emerge from a single coinfected cell. Not only does segmentation enhance genetic diversification but it plays a unique role in the evolutionary history of segmented viruses due to the rare occasions when a reassortant is successful at a population scale. A striking example from the Bunyaviridae family of the emergence of a novel virus through reassortment is that of Ngari virus. For influenza A (IAV), the best characterised segmented virus, reassortment has facilitated the formation of pandemic strains in 1957, 1968 and 2009. Out of seven epidemic-prone diseases prioritized by the WHO 2018 R&D Blueprint as public health emergencies with an urgent need for accelerated research, three are Bunyaviruses: Lassa, Rift Valley and Crimean-Congo hemorrhagic fevers. Thus, the overarching hypothesis of this project is that reassortment of segmented viruses plays a major role not only to drive their diversification and evolution, but to dramatically alter their ecology and transmission dynamics. Specifically, we aim to 1) develop mathematical models of the intracellular life cycle for a family of segmented viruses to quantify for the first time their viral replication dynamics and reassortment frequencies, and 2) develop standardised sequencing protocols and novel phylogenetic methods to quantify the evolutionary and epidemiological implications of reassortment for Crimean-Congo hemorrhagic fever virus (CCHFV). A biobank with clinical and field samples from CCHFV endemic regions in Turkey and Tajikistan will be set up in this project. Clinical and field data will be leveraged to ensure our methods and results have the potential to inform public health strategies, predict outbreak risk and contribute to the One Health approach for the prevention and control of CCHF disease.

基因组分割对于病毒基因表达控制和 RNA 组装成新生病毒颗粒具有重要意义。它还创造了重配的潜力：在共感染同一细胞的病毒之间交换完整的基因片段。重配与重组不同，因为它允许从单个共感染细胞中出现许多不同的基因型。分段不仅增强了遗传多样性，而且由于重配在群体规模上成功的罕见情况，它在分段病毒的进化史上发挥着独特的作用。布尼亚病毒科中通过重配出现新型病毒的一个引人注目的例子是阿里病毒。对于甲型流感（IAV）这种特征最鲜明的分段病毒，重配促进了 1957 年、1968 年和 2009 年大流行毒株的形成。世界卫生组织 2018 年研发蓝图将七种易流行疾病列为迫切需要的突发公共卫生事件为了加速研究，三种是布尼亚病毒：拉沙病毒、裂谷病毒和克里米亚-刚果出血热。因此，该项目的总体假设是，分段病毒的重配不仅在推动其多样化和进化方面发挥着重要作用，而且还极大地改变了其生态和传播动态。具体来说，我们的目标是 1) 开发分段病毒家族的细胞内生命周期数学模型，以首次量化其病毒复制动态和重配频率，2) 开发标准化测序方案和新颖的系统发育方法来量化进化克里米亚-刚果出血热病毒（CCHFV）重配的流行病学意义。该项目将建立一个生物库，其中包含来自土耳其和塔吉克斯坦CCHFV流行地区的临床和现场样本。将利用临床和现场数据来确保我们的方法和结果有可能为公共卫生策略提供信息、预测疫情风险并为预防和控制 CCHF 疾病的“同一个健康”方法做出贡献。