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<p>SARS-CoV-2, like many viruses, generates syncytia but the role of syncytia formation in viral evolution remains unknown. Using SARS-CoV-2 and SARS-CoV-2 Spike (S) replacement vesicular stomatitis (VSV), we show that S-mediated syncytia impair the antiviral effects of interferons in cultured cells, human lung cell cultures, and hACE2 transgenic mice. Amino acid substitutions that modulate syncytia formation in Delta- and Omicron-encoded S have parallel effects on viral interferon resistance. S-mediated syncytia compromise antibody-mediated virus neutralization in cultured cells. We recapitulate interferon and neutralizing antibody resistance in syncytia generated by the orthoreovirus p14 fusion-associated small transmembrane (FAST) protein in VSV, influenza virus, and seasonal coronavirus OC43 infections. These findings explain selection of SARS-CoV-2 fusogenic variants in humans and, more generally, the evolution of fusogenic viruses driven by adaptive and innate immunity.</p>

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Viral syncytia evolve to resist interferon

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月20日

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  • Tiansheng Li,
  • Insung Kang,
  • Juan Ye,
  • Zhe Hu,
  • James Gibbs,
  • Chengjin Ye,
  • Kazuyo Takeda,
  • Ivan Kosik,
  • Guoli Shi,
  • Jaroslav Holly,
  • Martina Kosikova,
  • Zhiping Ye,
  • Alex A. Compton,
  • Luis Martinez-Sobrido,
  • Reed F. Johnson,
  • Hang Xie,
  • Jonathan W. Yewdell

摘要

SARS-CoV-2, like many viruses, generates syncytia but the role of syncytia formation in viral evolution remains unknown. Using SARS-CoV-2 and SARS-CoV-2 Spike (S) replacement vesicular stomatitis (VSV), we show that S-mediated syncytia impair the antiviral effects of interferons in cultured cells, human lung cell cultures, and hACE2 transgenic mice. Amino acid substitutions that modulate syncytia formation in Delta- and Omicron-encoded S have parallel effects on viral interferon resistance. S-mediated syncytia compromise antibody-mediated virus neutralization in cultured cells. We recapitulate interferon and neutralizing antibody resistance in syncytia generated by the orthoreovirus p14 fusion-associated small transmembrane (FAST) protein in VSV, influenza virus, and seasonal coronavirus OC43 infections. These findings explain selection of SARS-CoV-2 fusogenic variants in humans and, more generally, the evolution of fusogenic viruses driven by adaptive and innate immunity.