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

• 批准号: 10653884
• 负责人: Carmen Molina-Paris
• 金额: $ 44.76万
• 依托单位: TRIAD NATIONAL SECURITY, LLC
• 依托单位国家: 美国
• 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/10653884
• 关键词: Acceleration; Address; Affect; Arthropods; Bunyaviridae; Cells; Clinical; Crimean Hemorrhagic Fever; Crimean-Congo Hemorrhagic Fever Virus; Data; Data Collection; Data Set; Disease; Ecology; Ensure; Epidemic; Epidemiology; Evolution; Family; Frequencies; Gene Expression; Genes; Genetic Enhancement; Genetic Recombination; Genomic Segment; 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; Role; Sampling; Standardization; Tajikistan; Ticks; Time; Vertebrates; Viral Genes; Virion; Virus; Virus Replication; Work; biobank; improved; laboratory experiment; mathematical model; novel; novel virus; outbreak concern; outbreak prediction; pandemic disease; public health emergency; research and development; transmission process; vector; viral transmission

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.

基因组分割对病毒基因表达控制和RNA组装成新生病毒体具有重要意义。它还创造了重组的可能性：在共同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，因为它允许许多不同的基因型从单个共感染细胞中出现。分段不仅增强了遗传多样性，而且由于在群体规模上成功复制的罕见情况，它在分段病毒的进化史中发挥着独特的作用。布尼亚病毒科通过重组产生新病毒的一个突出例子是阿里病毒。对于甲型流感（IAV），最具特征的分段病毒，重配促进了1957年，1968年和2009年大流行毒株的形成。在世卫组织2018年研发蓝图优先考虑的7种易感染疾病中，有3种是布尼亚病毒：拉沙病毒、裂谷热和克里米亚-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力学。具体而言，我们的目标是1）开发一个分段病毒家族的细胞内生命周期的数学模型，以首次量化其病毒复制动力学和重配频率，以及2）开发标准化的测序方案和新的系统发育方法，以量化克里米亚-刚果出血热病毒（CCHFV）重配的进化和流行病学影响。该项目将建立一个生物库，储存土耳其和塔吉克斯坦CCHFV流行地区的临床和现场样本。临床和现场数据将被利用，以确保我们的方法和结果有可能为公共卫生战略提供信息，预测爆发风险，并为预防和控制CCHF疾病的One Health方法做出贡献。