FHL1 is a major host factor for chikungunya virus infection

Chikungunyavirus (CHIKV) is a re-emerging alphavirusthat is transmitted to humans by mosquito bitesand causes musculoskeletal and joint pain1,2. Despite intensive investigations, the human cellular factors that are critical for CHIKV infection remain unknown, hampering the understanding of viral pathogenesisand the development of anti-CHIKV therapies. Here we identified the four-and-a-half LIM domainprotein 1 ( FHL1)3 as a host factorthat is required for CHIKV permissiveness and pathogenesis in humans and mice. Ablation of FHL1expression results in the inhibition of infection by several CHIKV strains and o’nyong-nyong virus, but not by other alphaviruses and flaviviruses. Conversely, expression of FHL1promotes CHIKV infection in cells that do not normally express it. FHL1interacts directly with the hypervariable domain of the nsP3 protein of CHIKV and is essential for the replication of viral RNA. FHL1is highly expressed in CHIKV-target cells and is particularly abundant in muscles3,4. Dermal fibroblastsand muscle cells derived from patients with Emery–Dreifuss muscular dystrophythat lack functional FHL15 are resistant to CHIKV infection. Furthermore, CHIKV infection is undetectable in Fhl1-knockout mice. Overall, this study shows that FHL1is a key factor expressed by the host that enables CHIKV infection and identifies the interaction between nsP3 and FHL1as a promising target for the development of anti-CHIKV therapies. FHL1is a key factor expressed by humans and mice that is required for chikungunyavirus infection and is therefore a promising target for the development of therapies against chikungunyavirus.