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 may drive the emergence of these novel variants, studies documenting a critical a 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 5 viral lineages sampled during the course of the global outbreak that included ancestral and emerging variants. Our data revealed increased interferon resistance in emerging SARS-CoV-2 variants, indicating that evasion of innate immunity is a significant driving force for SARS-CoV-2 evolution. These findings have implications for the increased lethality of emerging variants and highlight the interferon subtypes that may be most successful in the treatment of early infections.

A stem-loop RNA RIG-I agonist confers prophylactic and therapeutic protection against acute and chronic SARS-CoV-2 infection in mice

“…Here, we showed that SLR14 potently prevented morbidity and mortality following infection with clinically relevant VOC, which have vastly different signature mutations and immune-evading capacity. Consistent with a recent study examining IFN-I potency against different variants in vitro 38 , the protective capacity of SLR14 was less impressive when administered against B.1.351 or B.1.1.7. Importantly, SLR14 still retained considerable residual antiviral capacity, which may be attributed by the speed, magnitude, and diversity of IFN-I responses induced by SLR14 that could collectively overcome viral resistance 19 .…”

“…5e-g ). Consistent with the reported resistance to IFN-I signaling in vitro 38 , SLR14 treatment was less effective against infection with B.1.351 or B.1.1.7 in vivo , conferring approximately 40 to 50% net protection in K18-hACE2 mice (60% survival in SLR14-treated mice over 10 to 20% survival in vehicle controls) ( Fig. 5h-m ).…”

“…As SARS-CoV-2 variants continue to emerge and spread, antiviral therapeutics that confer broadly cross-reactive protection are urgently needed. Emerging evidence suggests that several SARS-CoV-2 variants have acquired mutations that confer elevated resistance to IFN-I treatment in cell culture 38 . However, whether such altered properties in vitro translate into evasion of IFN-based therapy in vivo remains unclear.…”

A phylogeny-based metric for estimating changes in transmissibility from recurrent mutations in SARS-CoV-2

“…While the exact function of this deletion remains to be determined, NSP6 has been shown to play an important role in innate immune response, suppressing IFN-I response 63 . Consistent with this finding, it has been proposed that evasion of innate immunity may be a significant driving force underlying SARS-CoV-2 evolution 64 .…”

Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant

“…This may be due to the shared Spike mutation D614G in IC19 and B.1.1.7, but not VIC, which is associated with enhanced transmissibility and increased entry efficiency [29][30][31] . Indeed, D614G has been associated with resistance to a range of Type I and III IFNs across several SARS-CoV-2 lineages, and contributes to the enhanced IFN-evasion of B.1.1.7 32 . Type I IFN restriction of SARS-CoV-2 is mediated in part by interferon induced membrane protein 2 (IFITM2) suppression of viral entry, and IFITM2 sensitivity is influenced by the Spike sequence 33,34 .…”