How are bunyavirus replication factories built?

The bunyavirus group of segmented RNA viruses includes pathogens capable of serious or fatal disease in both animals and humans. As evidence of their threat to human health, the WHO lists several bunyaviruses as posing high risk of causing Public Health Emergencies of International Concern. Following infection, bunyaviruses initiate a cascade of events that convert the host cell into a virion production line, historically-termed a viral factory (VF), and the ensuing anabolic events of transcription, translation, replication and virion assembly are at the very heart of virus infectivity and thus disease. However, spatio-temporal and structural information of VF formation, as well as information of critical host factor involvement, are either lacking, or incorrect. We propose to determine how the bunyavirus VF is built through three goals: 1)We will determine where and when discrete functional stages of bunyavirus multiplication cycles occur; 2)We will identify host factors involved in VF formation and activity, using genome-wide and machine learning approaches; 3)We will determine the molecular organisation of bunyavirus VFs in close-to-native conditions integrating functional information and host factor involvement, using correlative light and cryo-EM approaches. Achieving these goals will greatly facilitate downstream identification of both viral and host targets for anti-bunyaviral therapies.