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

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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.