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

• Published in: Nature communications Vol. 15; no. 1; pp. 5426 - 11
• Main Authors: Veit, Ethan C., Salim, Madihah S., Jung, Mariel J., Richardson, R. Blake, Boys, Ian N., Quinlan, Meghan, Barrall, Erika A., Bednarski, Eva, Hamilton, Rachael E., Kikawa, Caroline, Elde, Nels C., García-Sastre, Adolfo, Evans, Matthew J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.06.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 49/109; 631/181/2481; 631/250/255/2514; 631/250/262; 631/326/596/2557; 64; 82/29; 82/80; Amino acid sequence; Amino acids; Animals; Antagonism; Dengue fever; Dengue Virus - genetics; Dengue Virus - physiology; Disease resistance; Evolution; Evolution, Molecular; Flavivirus - genetics; Flavivirus - physiology; Host-Pathogen Interactions - genetics; Humanities and Social Sciences; Humans; Interferon; Mammals; Mice; multidisciplinary; Pathogenesis; Phylogeny; Proteins; Science; Science (multidisciplinary); Stat2 protein; STAT2 Transcription Factor - genetics; STAT2 Transcription Factor - metabolism; Tropism; Vector-borne diseases; Vertebrates; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; Viremia; Viruses; Zika virus; Zika Virus - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49758-0

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. Zika and Dengue virus non-structural protein 5 can antagonise STAT2 modulating the host response and this interaction is involved in determining tropism. Here the authors show mammals independently evolved resistance to flavivirus NS5 multiple times, involving complex genetic changes in STAT2 which balance viral defence whilst maintaining STAT2’s critical functions.