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Significance
In just over 2 years, SARS-CoV-2 has infected 500 million people, causing more than 6 million COVID-19 deaths. High infection rates have provided substantial opportunities for the virus to evolve, as variants with enhanced transmissibility, pathogenesis, and resistance to neutralizing antibodies have emerged. While much focus has centered on the Spike protein, mutations were also detected in other viral proteins that may inhibit the interferons, two of which, IFNα2 and IFNβ, are being repurposed for COVID-19 treatment. Here, we compared the potency of diverse human interferons against ancestral and emerging variants of SARS-CoV-2. Our data revealed increased interferon resistance in SARS-CoV-2 variants of concern, suggesting a significant but underappreciated role for innate immunity in driving the next phase of the COVID-19 pandemic.
Abstract
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.
Published in PNAS (July 22, 2022):
