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

Wern Hann Ng, Xiang Liu, Zheng L. Ling, Camilla N. O. Santos, Lucas S. Magalhães, Andrew J. Kueh, Marco J. Herold, Adam Taylor, Joseph R. Freitas, Sandra Koit, Sainan Wang, Andrew R. Lloyd, Mauro M. Teixeira, Andres Merits, Roque P. Almeida, Nicholas J. C. King and Suresh Mahalingam ()
Additional contact information
Wern Hann Ng: Griffith University
Xiang Liu: Griffith University
Zheng L. Ling: The University of Sydney
Camilla N. O. Santos: University Hospital/EBSERH, Federal University of Sergipe (UFS)
Lucas S. Magalhães: University Hospital/EBSERH, Federal University of Sergipe (UFS)
Andrew J. Kueh: The Walter and Eliza Hall Institute of Medical Research
Marco J. Herold: The Walter and Eliza Hall Institute of Medical Research
Adam Taylor: Griffith University
Joseph R. Freitas: Griffith University
Sandra Koit: University of Tartu
Sainan Wang: University of Tartu
Andrew R. Lloyd: University of New South Wales
Mauro M. Teixeira: Universidade Federal de Minas Gerais
Andres Merits: University of Tartu
Roque P. Almeida: University Hospital/EBSERH, Federal University of Sergipe (UFS)
Nicholas J. C. King: Griffith University
Suresh Mahalingam: Griffith University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-42330-2

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