FHL1 promotes chikungunya and o'nyong-nyong virus infection and pathogenesis with implications for alphavirus vaccine design

Arthritogenic alphaviruses are positive-strand RNA viruses that cause debilitating musculoskeletal diseases affecting millions worldwide. A recent discovery identified the four-and-a-half-LIM domain protein 1 splice variant A (FHL1A) as a crucial host factor interacting with the hypervariable domain (HVD) of chikungunya virus (CHIKV) nonstructural protein 3 (nsP3). Here, we show that acute and chronic chikungunya disease in humans correlates with elevated levels of FHL1. We generated FHL1-/- mice, which when infected with CHIKV or o'nyong-nyong virus (ONNV) displayed reduced arthritis and myositis, fewer immune infiltrates, and reduced proinflammatory cytokine/chemokine outputs, compared to infected wild-type (WT) mice. Interestingly, disease signs were comparable in FHL1-/- and WT mice infected with arthritogenic alphaviruses Ross River virus (RRV) or Mayaro virus (MAYV). This aligns with pull-down assay data, which showed the ability of CHIKV and ONNV nsP3 to interact with FHL1, while RRV and MAYV nsP3s did not. We engineered a CHIKV mutant unable to bind FHL1 (CHIKV-Delta FHL1), which was avirulent in vivo. Following inoculation with CHIKV-Delta FHL1, mice were protected from disease upon challenge with CHIKV and ONNV, and viraemia was significantly reduced in RRV- and MAYV-challenged mice. Targeting FHL1-binding as an approach to vaccine design could lead to breakthroughs in mitigating alphaviral disease. FHL1A is a crucial host factor for alphavirus infection but its impact on pathogenesis is unclear. Here, the authors use a FHL1-/- knockout mouse model to show that the FHL1 splice variant impacts arthritis and myositis after chikungunya or o'nyong-nyong infections but not Ross River or mayaro virus infection.

Automated summary

This study reveals the importance of FHL1 as a crucial host factor for chikungunya virus (CHIKV) and o'nyong-nyong virus (ONNV) infections. Elevated levels of FHL1 are correlated with acute and chronic CHIKV disease in humans. Using FHL1-/- mice, the authors demonstrate that FHL1 impacts arthritis and myositis after CHIKV and ONNV infections, but has no effect on Ross River virus (RRV) or mayaro virus (MAYV) infections. Furthermore, a CHIKV mutant unable to bind FHL1 is avirulent and provides protection against CHIKV and ONNV challenges.