Harnessing host factors associated with virus induced structures to design antiviral strategies against Orthonairoviruses

"The public health risks associated with new and emerging viral infectious diseases are now well known. Most of these diseases are caused by zoonotic viruses whose reservoirs/vectors are animals, particularly arthropods. Among pathogens transmitted by ticks, the Orthonairovirus genus harbors over 50 viruses assigned to 15 groups/species, some being highly pathogenic for humans and animals. Among them, the Crimean-Congo hemorrhagic fever virus (CCHFV) is the virus that combines both the largest range and the highest medical importance, with several thousands human cases each year and a high mortality rate estimated on average at 30% and with a circulation in tick and cattle in France. To date, no prophylactic treatment has been developed against CCHFV nor against other orthonairoviruses. In this context, it is crucial and urgent to develop both fundamental and translational studies on these pathogens in order to design the first prophylactic and therapeutic treatments against CCHFV and other orthonairoviruses, to understand the molecular basis of its inter-species transmission, and to anticipate, not just react to infectious threat. In this context, the VISTA project proposes to discover and characterize host factors required for viral life cycle of three orthonairoviruses, including CCHFV but also HAZV and AIGV, with a focus on factors recruited in two virus-induced structures. These structures are on the one hand, the viral particles themselves and on the other hand, viral 'condensates' concentrating the viral proteins NP and L, two key proteins for viral replication. By combining imaging and affinity purification coupled to mass-spectrometry, the VISTA project will investigate these structures in three different hosts, namely Human, Tick and Bovine, allowing an interspecific investigation of viral determinants and factors of transmission. The VISTA project will also investigate the role and properties of the viralinduced structures obtained in these latter hosts. Finally, after their identification and characterization, the VISTA project will test molecules that could target these factors in order to lay the foundations of the discovery of host-directed antivirals."