Interferon resistance of emerging SARS-CoV-2 variants

Proc Natl Acad Sci U S A. 2022 Aug 9;119(32):e2203760119. doi: 10.1073/pnas.2203760119. Epub 2022 Jul 22.


The emergence of SARS-CoV-2 variants with enhanced transmissibility, pathogenesis, and resistance to vaccines presents urgent challenges for curbing the COVID-19 pandemic. While Spike mutations that enhance virus infectivity or neutralizing antibody evasion may drive the emergence of these novel variants, studies documenting a critical role for interferon responses in the early control of SARS-CoV-2 infection, combined with the presence of viral genes that limit these responses, suggest that interferons may also influence SARS-CoV-2 evolution. Here, we compared the potency of 17 different human interferons against multiple viral lineages sampled during the course of the global outbreak, including ancestral and five major variants of concern that include the B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), B.1.617.2 (delta), and B.1.1.529 (omicron) lineages. Our data reveal that relative to ancestral isolates, SARS-CoV-2 variants of concern exhibited increased interferon resistance, suggesting that evasion of innate immunity may be a significant, ongoing driving force for SARS-CoV-2 evolution. These findings have implications for the increased transmissibility and/or lethality of emerging variants and highlight the interferon subtypes that may be most successful in the treatment of early infections.

Keywords: COVID-19; SARS-CoV-2; innate immunity; interferons; variants of concern.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibodies, Neutralizing
  • Antiviral Agents* / pharmacology
  • Antiviral Agents* / therapeutic use
  • COVID-19* / immunology
  • COVID-19* / prevention & control
  • COVID-19* / transmission
  • Humans
  • Interferons* / pharmacology
  • Interferons* / therapeutic use
  • SARS-CoV-2* / drug effects
  • SARS-CoV-2* / genetics
  • SARS-CoV-2* / immunology
  • Spike Glycoprotein, Coronavirus / genetics


  • Antibodies, Neutralizing
  • Antiviral Agents
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Interferons

Supplementary concepts

  • SARS-CoV-2 variants