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

基因组分割对于病毒基因表达调控和RNA组装成新生病毒粒子具有重要意义。它还创造了重新分类的可能性：在共同感染同一细胞的病毒之间交换完整的基因片段。重组不同于重组，因为它允许从一个合并感染的细胞中出现许多不同的基因类型。片段不仅增强了遗传多样性，而且由于重组在种群规模上成功的罕见情况，它在片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出现一种新病毒的一个显著例子是阿里病毒。对于甲型流感病毒(IAV)这一最具特征的节段性病毒，重新分类促进了1957、1968和2009年大流行毒株的形成。在世卫组织2018年研发蓝图列为迫切需要加快研究的突发公共卫生事件的七种疫情高发疾病中，有三种是本雅热病毒：拉萨病毒、裂谷病毒和克里米亚-刚果出血热。因此，该项目的首要假设是，节段病毒的重新分类不仅在推动它们的多样化和进化方面发挥着重要作用，而且还显著改变了它们的生态和传播动态。具体地说，我们的目标是1)为一个分段病毒家族建立细胞内生命周期的数学模型，以首次量化它们的病毒复制动力学和重新分类频率，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)重新分类的进化和流行病学意义。该项目将建立一个生物库，其中包括来自土耳其和塔吉克斯坦CCHFV流行区的临床和现场样本。我们将利用临床和现场数据，确保我们的方法和结果有可能为公共卫生战略提供信息，预测暴发风险，并为预防和控制CCHF疾病的统一健康方法做出贡献。

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.