Fig. 5: Antagonism of innate immune activation by Alpha.

SARS-CoV-2 Alpha has evolved more effective innate immune antagonisms. First-wave isolates activate a delayed innate response in airway epithelial cells relative to rapid viral replication, indicative of viral innate immune antagonism early in infection. The known innate immune antagonists Orf9b, Orf6 and N act at different levels to inhibit RNA sensing. Orf6 inhibits IRF3 and STAT1 nuclear translocation^12,13; N prevents activation of the RNA sensor RIG-I³³; and Orf9b inhibits RNA sensing through interaction with TOM70, regulated by phosphorylation. Alpha has evolved to produce more sgRNA for these key innate immune antagonists, which leads to increased protein levels and enhanced innate immune antagonism as compared to first-wave isolates. gRNA, genomic RNA.