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Study of the impact of genetic diversity of the Rift Valley fever virus on its virulence and replication cycle

Rift Valley Fever (RVF) is a vector-borne disease mainly transmitted by mosquitoes. In ruminants, RVF is responsible for high neonatal mortality and numerous abortions, with important economic consequences for the affected countries. The circulation of RVFV is particularly active in West African countries (Senegal/Mauritania) where the disease is endemic.

Firstly, in order to assess the virulence of circulating RVFV strains, two field strains were studied: strain MRU25010-30 of camel origin isolated in northern Mauritania (2010) and strain MRU2687-3 of goat origin from southern Mauritania (2013). Their replicative capacities and virulence were determined in vivo in BALB/c mice and in vitro on several cell types such as human hepatocytes (HepaRG), induced pluripotent stem cells (hiPSC) differentiated into neural cells (astrocytes, neurons, and oligodendrocytes) and human lung cells (A549, adenocarcinoma). In the mouse model, we tested two routes of inoculation: intranasal (IN) or subcutaneous (SC). Regardless of the route of inoculation, SC or IN, MRU25010-30 induced earlier mortality in BALB/c mice (D3/4 p.i.) compared to MRU2687-3 (D8/10 p.i.). This mortality induced by MRU25010-30 is associated with a high viral load in the liver of infected mice and early detection of the virus in the brain. In the different cell models studied, MRU25010-30 induced a 10- to 100-fold higher infectious titer than MRU2687-3. Deep sequencing revealed that these two strains belong to two distinct genetic lineages of RVFV and exist as viral subpopulations. Using reverse genetics, we showed that a single genetic segment (the M segment) is responsible for the differences in replication dynamics. The exploration of the intra-strain diversity of the M segment allowed the identification of two viral genetic markers influencing the viral replication of these strains in vitro: one located in the envelope glycoprotein Gn and the other in the untranslated region of the M segment

This work has enabled the characterization of key molecular determinants within RVFV genome of two field strains. The characterization of their mechanism of action should ultimately lead to a better understanding of RVFV-induced virulence and pathogenesis. This work also provides an interesting basis to study the role of RVFV Gn protein in the viral cycle and the regulation of the expression of the viral protein encoded by the M segment.

 Mehdi has done his PhD in the BUNYA team, under the supervision of Drs Frederick Arnaud, Maxime Ratinier et de Catherine Cetre-Sossah