Interferon resistance of emerging SARS-CoV-2 variants

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.

Omicron-induced interferon signalling prevents influenza A virus infection

“…Data on the severity of SARS-CoV-2/ influenza A virus co-infections are inconsistent in cell culture and animal models [Andrés et al, 2022;Kim EH et al, 2022;Kim HK et al, 2022;Oishi et al, 2022] and in humans [Cuadrado-Payán et al, 2020;Yue et al, 2020;Alosaimi et al, 2021;Stowe et al, 2021;Xiang et al, 2021;Krumbein et al, 2022;Swets et al, 2022]. This may not be a surprise, given the differences in interferon signalling between different SARS-CoV-2 variants that we present here and that were described in previous studies [Alfi et al, 2022;Bojkova et al, 2022;Bojkova et al, 2022a;Guo et al, 2022;Thorne et al, 2022]. Future studies may have to include more different virus variants and strains to establish a clearer picture.…”

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

“…Viruses have evolved highly successful mechanisms to block IFN-stimulated gene production in order to control and counteract IFN antiviral signaling [ 109 ]. The Japanese encephalitis virus (JEV) flavivirus is highly efficient in blocking the IFN-induced activation of JAK-STAT signaling cascade [ 110 ], while IFN inhibition, resistance, attenuation, and evasion by SARS-CoV-2 and variants via various mechanisms have been reported in great detail [ 54 , 111 , 112 , 113 , 114 , 115 ]. Deficiencies in the first line IFN defense system may result in impaired type I IFN responses resulting in high blood viral load that are often associated with severe and critical COVID-19 patients [ 116 ], while the JAK-STAT signaling pathway may also be suppressed during post-infection by persistent viral reservoirs.…”

Pharmacological modulators of epithelial immunity uncovered by synthetic genetic tracing of SARS-CoV-2 infection responses

“…Viral infections are detected through pattern recognition receptors, including RIG-I-like receptors. Importantly, SARS-CoV-2 evolution through variants of concern involved increased interferon response evasion 24 and a synthetic agonist stimulation of RIG-I protects mice from acute and chronic SARS-CoV-2 infection, even in absence of the adaptive immune system 25 . This underscores the importance of epithelial innate immune responses to restrain SARS-CoV-2 infection and supports the identification of pharmacological modulators of such response as a therapeutic strategy for COVID-19 and viral infection more broadly.…”