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Evolution of STAT2 resistance to flavivirus NS5 occurred multiple times despite genetic constraints

Author

Listed:
  • Ethan C. Veit

    (Icahn School of Medicine at Mount Sinai)

  • Madihah S. Salim

    (Icahn School of Medicine at Mount Sinai)

  • Mariel J. Jung

    (Icahn School of Medicine at Mount Sinai)

  • R. Blake Richardson

    (Icahn School of Medicine at Mount Sinai)

  • Ian N. Boys

    (University of Utah
    Howard Hughes Medical Institute)

  • Meghan Quinlan

    (University of Utah
    Howard Hughes Medical Institute)

  • Erika A. Barrall

    (Icahn School of Medicine at Mount Sinai)

  • Eva Bednarski

    (Icahn School of Medicine at Mount Sinai)

  • Rachael E. Hamilton

    (Icahn School of Medicine at Mount Sinai)

  • Caroline Kikawa

    (University of Washington
    University of Washington
    Fred Hutch Cancer Center)

  • Nels C. Elde

    (University of Utah
    Howard Hughes Medical Institute)

  • Adolfo García-Sastre

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Matthew J. Evans

    (Icahn School of Medicine at Mount Sinai)

Abstract

Zika and dengue virus nonstructural protein 5 antagonism of STAT2, a critical interferon signaling transcription factor, to suppress the host interferon response is required for viremia and pathogenesis in a vertebrate host. This affects viral species tropism, as mouse STAT2 resistance renders only immunocompromised or humanized STAT2 mice infectable. Here, we explore how STAT2 evolution impacts antagonism. By measuring the susceptibility of 38 diverse STAT2 proteins, we demonstrate that resistance arose numerous times in mammalian evolution. In four species, resistance requires distinct sets of multiple amino acid changes that often individually disrupt STAT2 signaling. This reflects an evolutionary ridge where progressive resistance is balanced by the need to maintain STAT2 function. Furthermore, resistance may come with a fitness cost, as resistance that arose early in lemur evolution was subsequently lost in some lemur lineages. These findings underscore that while it is possible to evolve resistance to antagonism, complex evolutionary trajectories are required to avoid detrimental host fitness consequences.

Suggested Citation

  • Ethan C. Veit & Madihah S. Salim & Mariel J. Jung & R. Blake Richardson & Ian N. Boys & Meghan Quinlan & Erika A. Barrall & Eva Bednarski & Rachael E. Hamilton & Caroline Kikawa & Nels C. Elde & Adolf, 2024. "Evolution of STAT2 resistance to flavivirus NS5 occurred multiple times despite genetic constraints," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49758-0
    DOI: 10.1038/s41467-024-49758-0
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    References listed on IDEAS

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    1. Takuya Iwamura & Adriana Guzman-Holst & Kris A. Murray, 2020. "Accelerating invasion potential of disease vector Aedes aegypti under climate change," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
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