Differential innate immune activation by wild-type and NSs-deficient RVFV strains in human blood monocytes.

Rift Valley fever virus (RVFV) is a Phlebovirus causing febrile and haemorrhagic illness in ruminants and humans. The viral protein NSs is a major virulence factor that suppresses the IFN-β response in various hosts. Hence, RVFV variants lacking functional NSs, such as Clone 13, are highly attenuated. It is speculated that from the sites of infection, the virus disseminates to the target organs via the bloodstream. We hypothesized that primary infection of circulating immune cells and their response to infection are critical factors determining systemic RVFV spread and pathogenesis. Human PBMC from healthy blood donors were exposed to both wild-type (WT) RVFV and Clone 13 strains. Flow cytometric analysis revealed that monocytes expressing LRP1, a known RVFV receptor, are target cells for RVFV. RNA-seq analysis of monocytes exposed to WT and Clone 13 strains showed a large number of differentially expressed genes compared to mock-exposed cells. Various genes involved in antiviral immune mechanisms were specifically modulated in monocytes either in response to WT or Clone 13 infection. Expression of genes encoding key inflammatory mediators, such as CCL2, CD40, and CD83, was only upregulated in Clone 13-infected monocytes, whereas IFNB1 and NFKB1 were downregulated specifically in WT-infected monocytes. Taken together, our findings suggest that RVFV NSs dampen the innate immune responses in monocytes which may be critical not only in RVFV pathogenesis but also in the induction of virus-specific immune response.