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

Author

Listed:
  • Wern Hann Ng

    (Griffith University
    Griffith University
    Griffith University)

  • Xiang Liu

    (Griffith University
    Griffith University
    Griffith University)

  • Zheng L. Ling

    (The University of Sydney
    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
    The University of Melbourne)

  • Marco J. Herold

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Adam Taylor

    (Griffith University
    Griffith University
    Griffith University)

  • Joseph R. Freitas

    (Griffith University
    Griffith University
    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
    The University of Sydney
    The University of Sydney)

  • Suresh Mahalingam

    (Griffith University
    Griffith University
    Griffith University)

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.

Suggested Citation

  • 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 , 2023. "FHL1 promotes chikungunya and o’nyong-nyong virus infection and pathogenesis with implications for alphavirus vaccine design," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42330-2
    DOI: 10.1038/s41467-023-42330-2
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    References listed on IDEAS

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    1. Laurent Meertens & Mohamed Lamine Hafirassou & Thérèse Couderc & Lucie Bonnet-Madin & Vasiliya Kril & Beate M. Kümmerer & Athena Labeau & Alexis Brugier & Etienne Simon-Loriere & Julien Burlaud-Gailla, 2019. "FHL1 is a major host factor for chikungunya virus infection," Nature, Nature, vol. 574(7777), pages 259-263, October.
    2. Rong Zhang & Arthur S. Kim & Julie M. Fox & Sharmila Nair & Katherine Basore & William B. Klimstra & Rebecca Rimkunas & Rachel H. Fong & Hueylie Lin & Subhajit Poddar & James E. Crowe & Benjamin J. Do, 2018. "Mxra8 is a receptor for multiple arthritogenic alphaviruses," Nature, Nature, vol. 557(7706), pages 570-574, May.
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    1. Vasiliya Kril & Michael Hons & Celine Amadori & Claire Zimberger & Laurine Couture & Yara Bouery & Julien Burlaud-Gaillard & Andrei Karpov & Denis Ptchelkine & Alexandra L. Thienel & Beate M. Kümmerer, 2024. "Alphavirus nsP3 organizes into tubular scaffolds essential for infection and the cytoplasmic granule architecture," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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