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

• Published in: Nature communications Vol. 14; no. 1; p. 6605
• Main Authors: Ng, Wern Hann, Liu, Xiang, Ling, Zheng L., Santos, Camilla N. O., Magalhães, Lucas S., Kueh, Andrew J., Herold, Marco J., Taylor, Adam, Freitas, Joseph R., Koit, Sandra, Wang, Sainan, Lloyd, Andrew R., Teixeira, Mauro M., Merits, Andres, Almeida, Roque P., King, Nicholas J. C., Mahalingam, Suresh
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.10.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/21; 13/31; 14/19; 14/35; 14/63; 631/1647/334/1874/345; 631/250/590/1867; 631/326/596/1282; 631/326/596/2557; 64/110; 64/60; Alternative splicing; Arthritis; Chemokines; Chikungunya virus; Disease; Disease control; Humanities and Social Sciences; Immunization; Infections; Inflammation; Inoculation; multidisciplinary; Musculoskeletal diseases; Myositis; Pathogenesis; Proteins; Rivers; RNA viruses; Science; Science (multidisciplinary); Vaccines; Vector-borne diseases; Viremia; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42330-2

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-ΔFHL1), which was avirulent in vivo. Following inoculation with CHIKV-ΔFHL1, 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.