SARS-CoV-2 causes COVID-19, a disease that was originally characterized by atypical pneumonia, but later as the virus and population immunity evolved, manifested itself in various forms, ranging from mild self-resolving respiratory symptoms to severe outcomes involving multiple organs 1, 2, 3. Shortly after the discovery of SARS-CoV-2, it became evident that the virus elicited an imbalanced immune program at the infection site, characterized by a delayed and weak interferon (IFN) response and a rapid and robust inflammatory response 4, 5. This is a rather lethal combination, which, on one hand, allows unhindered virus replication in infected cells, and on the other hand, causes severe tissue damage due to ‘cytokine storm’ fueled by overactive inflammatory cells [6].

Research has demonstrated that SARS-CoV-2 interferes with IFN signaling through a coordinated action of viral proteins that impede multiple steps in the pathway. The SARS-CoV-2 genome encodes nearly 30 proteins, including 16 nonstructural (nonstructural protein 1–16), four structural (spike, S; envelope, E; membrane, M; and nucleocapsid, N), and several accessory proteins (open-reading frame (ORF) 3a, ORF3c, ORF6, ORF7a, ORF7b, ORF8, ORF9b, ORF9c, and ORF10) [7]. Overexpression studies have shown that almost all of these proteins participate, either directly or indirectly, in the blockade of the IFN pathway. The specific contributions of each viral protein to IFN inhibition and their mechanism(s) of action are detailed in comprehensive reviews available elsewhere 8••, 9, 10.

As it relates to IFN antagonism, SARS-CoV-2 proteins can be categorized into two groups. The first group comprises structural and nonstructural proteins, which are essential for virus replication and biogenesis but, as a second job, play important roles in IFN inhibition. Owing to their conserved and critical functions in the virus lifecycle, these proteins demonstrate limited tolerance for mutations that could boost their immune-antagonizing capabilities yet compromise their vital roles in virus propagation. The second group consists of accessory proteins, which are dispensable for virus replication but crucial for creating a favorable host environment by ablating host defense mechanisms. These proteins, free from the constraints of essential functions, have more evolutionary freedom to respond to increasing selection pressures imposed by host defenses, providing a selective advantage to SARS-CoV-2 11, 12.

As the COVID-19 pandemic pressed on, SARS-CoV-2 underwent continued evolution, generating variants with distinct genotypes and phenotypes. Some variants, termed variants of concern (VOCs), exhibited an exceptional ability to spread rapidly, outcompeting existing viral lineages and triggering new waves of infections 13, 14. Notable VOCs include Alpha, Beta, Gamma, Delta, and Omicron. Several factors contributed to their dominance, including superior immune escape, altered tissue tropism, increased transmissibility, and enhanced evasion of the IFN pathway 15, 16••. Notably, nearly all major SARS-CoV-2 VOCs display heightened activity against type-I and -III IFNs compared with ancestral isolates 16••, 17•, 18, 19. This enhancement likely stems from genomic changes amplifying the expression and/or functions of specific IFN-antagonizing proteins in VOCs. Here, we spotlight two of these proteins, ORF6 and ORF9b, which, according to recent literature, exhibited elevated expression in certain SARS-CoV-2 variants, contributing to their increased fitness against IFN signaling.