Deciphering the host and viral factors governing the assembly mechanism of the Crimean-Congo hemorrhagic fever virus (CCHFV) and orthonairoviruses

"Tick-borne infectious diseases are on the rise worldwide, due to the geographical expansion of ticks. The Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus of the Nairoviridae family. It belongs to the risk group 4 (RG4) that needs to be studied in a BSL4 containment. CCHFV poses a major threat to public health because it causes severe hemorrhagic fevers associated with high case-fatality rates (10-40%), with possible human-to-human transmission, and because of the absence of approved therapeutic options or vaccines in the United States and the European Union. Until a few years ago, no cases of CCHFV had been reported in Western Europe. However, human cases detected in Spain, high seroprevalence rates in wildlife and the detection of multiple strains of CCHFV in ticks in France suggest that the enzootic cycle of CCHFV has already been established in certain regions of south-western Europe. It is essential to understand how the CCHFV particles assemble in infected cells in order to find treatments and anticipate the emergence of an epidemic. In this context, the CCHFabric project aims at characterizing the role of the non-structural viral proteins GP38 and NSm in the assembly and secretion of viral particles, and also at identifying and characterizing the role of the host factors involved. This project will combine structural biology, computational biology and cellular and molecular virology approaches to determine the assembly mechanisms of infectious viral particles. First, the project will focus on the cellular factors involved in assembly, by identifying the assembly site using microscopy approaches as well as the host factors involved using proteomic analyses, computational biology and molecular virology approaches. Secondly, the NSm protein will be characterized using structural approaches involving NMR, computational biology, and molecular/cellular virology. Finally, the GP38 protein will be studied in the form of the complex formed with the two CCHFV envelope glycoproteins, Gn and Gc, using structural biology techniques based on cryo-electron microscopy of whole viral particles and molecular virology in cellula. The knowledge acquired through these lines of research will enable us to develop and test molecules targeting the host factors, NSm and GP38, that we will test in cellula for their antiviral activity against CCHFV and other orthonairoviruses. The most promising molecules will be tested ex vivo and finally in vivo, in two small animal models. These results will reveal novel host pathways involved in CCHFV infection as well as the role of the viral proteins GP38 and NSm, which will provide a better understanding of the biology of this virus, and will highlight factors that could be targeted for therapeutic intervention. In addition, the methods and results obtained during this project will be easily transferred to the study of other orthonairoviruses, known or as yet unknown, with a high risk of passage to humans. Indeed, CCHFV is probably the first 'successful' orthonairovirus to have crossed the species-specific barrier and been transmitted to humans. There is no doubt that, due to the rapid spread of their tick vectors, other orthonairoviruses will soon cross this barrier and be transmitted to humans, generating related or as yet unknown diseases. In conclusion, the CCHFabric project will lead to a better understanding of viral assembly and secretion, with patentable discoveries concerning antiviral molecules and new therapeutic targets for CCHFV and related orthonairoviruses."