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

20-EEID US-UK 在新兴布尼亚病毒的细胞、临床和系统发育水平上进行建模重组

基本信息

批准号：
BB/W010755/1
负责人：
Grant Lythe
金额：
$ 251.24万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FW010755%2F1
关键词：
20 EEID US UK Modelling

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 quantitatively different from intramolecular recombination in that it allows many distinct genotypes to emerge from a single coinfected cell. Not only does segmentation enhance genetic diversification but it also plays a unique role in the evolutionary history of many segmented viruses due to the rare occasions when a reassortant is successful at the population scale. A striking example of the emergence of a novel virus through reassortment from the Bunyavirales is that of Ngari virus. For influenza (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 prioritised by the WHO 2018 R&D Blueprint as public health emergency with an urgent need for accelerated research, three are Bunyaviruses. 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 and together with in vitro experiments quantify for the first time their viral replication dynamics and reassortment frequencies, and 2) develop standardised protocols for sequencing, as well as 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 key CCHFV endemic regions in Turkey and Tajikistan will be set up in this project. Clinical and field data will be leveraged so that our methods and results have the potential to inform control strategies and predict outbreak risk. The quantitative methods developed in this project will contribute to the One Health approach advocated by Sorvillo et al. for CCHFV. Our goal is to develop novel mathematical and phylodynamic methods to quantify, at the cellular and the epidemic levels, reassortment frequency and fitness for segmented Bunyaviruses. This will enhance our understanding of CCHFV evolution and epidemiology in Turkey and Tajikistan. To achieve this goal, this US-UK collaborative project brings together expertise in phylogenetics, mathematical modelling, BSL-3 and BSL-4 capabilities, as well as field and clinical expertise in Turkey and Tajikistan with direct access to large collections of human, animal host and vector samples. We will quantify reassortment patterns, bringing together mathematical models with in vitro experiments of selected Bunyaviruses in arthropod and vertebrate cell lines. Statistical inference will allow us to estimate the basic reproduction number for each reassortant and cellular host. At the population level, we will design DNA sequencing and phylodynamic methods to dissect the evolutionary and transmission history of a segmented virus. Thus, our phylogenetic analysis of the field data to be collected in Turkey and Tajikistan will critically evaluate the convolution of point mutations, recombination and reassortment of CCHFV. Phylodynamic methods, adapted and developed in this project, together with field data, will allow us to relate these evolutionary processes to the host switching, temporal and geographical patterns of CCHFV outbreaks. With clinical information and data from Turkey and Tajikistan we will parameterise a mathematical model of CCHFV nosocomial transmission to inform public health decision making. While we focus on the Bunyaviridae family, especially CCHFV, our quantitative methods will be made adjustable to other segmented viruses of great public health relevance.

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。重配与分子内重组在数量上有所不同，因为它允许从单个共感染的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，它在许多分段病毒的进化史上也发挥着独特的作用。阿里病毒是通过布尼亚病毒目重配而出现的新型病毒的一个引人注目的例子。对于流感（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突发公共卫生事件，迫切需要加速研究，其中三种是布尼亚病毒。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，并结合体外实验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，如以及新的系统发育方法来量化克里米亚-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，其中包含土耳其和塔吉克斯坦 CCHFV 主要流行地区的临床和现场样本。将利用临床和现场数据，使我们的方法和结果有可能为控制策略提供信息并预测疫情风险。该项目开发的定量方法将有助于 Sorvillo 等人倡导的“同一个健康”方法。对于CCHFV。我们的目标是开发新的数学和系统动力学方法，以在细胞和流行水平上量化分段布尼亚病毒的重配频率和适应性。这将增强我们对土耳其和塔吉克斯坦 CCHFV 演变和流行病学的了解。为了实现这一目标，这个美英合作项目汇集了系统发育、数学建模、BSL-3 和 BSL-4 能力方面的专业知识，以及土耳其和塔吉克斯坦的现场和临床专业知识，可直接获取大量人类、动物样本宿主和载体样本。我们将量化重配模式，将数学模型与节肢动物和脊椎动物细胞系中选定的布尼亚病毒的体外实验结合起来。统计推断将使我们能够估计每个重配体和细胞宿主的基本繁殖数。在群体层面，我们将设计DNA测序和系统动力学方法来剖析分段病毒的进化和传播历史。因此，我们对在土耳其和塔吉克斯坦收集的现场数据进行的系统发育分析将严格评估 CCHFV 点突变、重组和重配的卷积。本项目中采用和开发的系统动力学方法与现场数据一起，将使我们能够将这些进化过程与 CCHFV 爆发的宿主转换、时间和地理模式联系起来。利用来自土耳其和塔吉克斯坦的临床信息和数据，我们将参数化 CCHFV 院内传播的数学模型，为公共卫生决策提供信息。虽然我们专注于布尼亚病毒科，尤其是 CCHFV，但我们的定量方法将适用于与公共卫生具有重大相关性的其他分段病毒。