Chikungunya virus (CHIKV) is a re-emerging Old World alphavirus transmitted to humans by mosquito bites which causes musculoskeletal and joint pain 1-3 . Despite intensive investigations, the identity of the human cellular factors critical for CHIKV infection remains elusive, hampering both the understanding of viral pathogenesis and the development of anti-CHIKV therapies. Here, we identified the Four-and-a-Half LIM domain protein 1 (FHL1) 4 as a host factor required for CHIKV permissiveness and pathogenesis. Ablation of FHL1 expression results in massive inhibition of infection by several CHIKV strains and O'nyong-nyong virus, but not by other alphaviruses or flaviviruses. Conversely, expression of FHL1 enhances infection of cells that do not express it and are poorly susceptible to CHIKV. We show that FHL1 directly interacts with the hypervariable domain of CHIKV nsP3 protein and is essential for viral RNA replication. FHL1 is highly expressed in CHIKV target cells and particularly abundant in muscles 4,5 . Significantly, dermal fibroblasts and muscle cells derived from Emery-Dreifuss muscular dystrophy (EDMD) patients which lack functional FHL1 6 are resistant to CHIKV infection. Importantly, CHIKV infection is undetectable in mice knocked out for the FHL1 gene. Overall, this study shows that FHL1 is a key host dependency factor for CHIKV infection and identifies nsP3-FHL1 interaction as a promising target for the development of anti-CHIKV therapies.

We recently identified the scaffolding RACK1 protein as an important host-dependency factor for dengue virus (DENV), a positive-stranded RNA virus responsible for the most prevalent mosquito-borne viral disease worldwide. Here, we have performed the first RACK1 interactome in human cells and identified Vigilin and SERBP1 as DENV host-dependency factors.