Mutations in SARS-CoV-2 variant nsp6 enhance type-I interferon antagonism

Cody J. Bills, Hongjie Xia, John Yun Chung Chen, Jason Yeung, Birte K. Kalveram, David Walker, Xuping Xie, Pei Yong Shi

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve after its emergence. Given its importance in viral infection and vaccine development, mutations in the viral Spike gene have been studied extensively; however, the impact of mutations outside the Spike gene are poorly understood. Here, we report that a triple deletion (ΔSGF or ΔLSG) in nonstructural protein 6 (nsp6) independently acquired in Alpha and Omicron sublineages of SARS-CoV-2 augments nsp6-mediated antagonism of type-I interferon (IFN-I) signaling. Specifically, these triple deletions enhance the ability of mutant nsp6 to suppress phosphorylation of STAT1 and STAT2. A parental SARS-CoV-2 USA-WA1/2020 strain containing the nsp6 ΔSGF deletion (ΔSGF-WA1) shows reduced susceptibility to IFN-I treatment in vitro, outcompetes the parental strain in human primary airway cultures, and increases virulence in mice; however, the ΔSGF-WA1 virus is less virulent than the Alpha variant (which has the nsp6 ΔSGF deletion and additional mutations in other genes). Analyses of host responses from ΔSGF-WA1-infected mice and primary airway cultures reveal activation of pathways indicative of a cytokine storm. These results provide evidence that mutations outside the Spike protein affect virus-host interactions and may alter pathogenesis of SARS-CoV-2 variants in humans.

Original languageEnglish (US)
Article number2209208
Pages (from-to)2209208
JournalEmerging Microbes and Infections
Issue number1
StatePublished - Dec 2023


  • SARS-CoV-2
  • cytokine storm
  • interferon
  • nsp6
  • variants

ASJC Scopus subject areas

  • Epidemiology
  • Parasitology
  • Microbiology
  • Immunology
  • Drug Discovery
  • Infectious Diseases
  • Virology


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