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

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, Adolfo García-Sastre and Matthew J. Evans ()
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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
Meghan Quinlan: University of Utah
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
Nels C. Elde: University of Utah
Adolfo García-Sastre: Icahn School of Medicine at Mount Sinai
Matthew J. Evans: Icahn School of Medicine at Mount Sinai

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49758-0

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