3-2-1- Evasion mechanisms by coronaviruses
CoVs have evolved several mechanisms to inhibit IFN-I induction (Cameron et al., 2012; Minakshi et al., 2009; Siu et al., 2009; Wathelet, Orr, Frieman, & Baric, 2007). To prevent IFN release, CoV proteins can inhibit several steps of the signal transduction pathway that bridge the interferon-α receptor 1 subunit (IFNAR1) and IFNAR2 to the STAT proteins that activate transcription. For SARS-CoV-1, these mechanisms include IFNAR1 degradation by ORF3a (Minakshi et al., 2009), decreased STAT1 phosphorylation by NSP1 (Wathelet et al., 2007), and antagonism of STAT1 nuclear translocation by ORF6 (Kopecky-Bromberg et al., 2007). However, SARS-CoV-2 ORF6 shares only 69% sequence homology with SARS-CoV-1, suggesting this function may not be conserved. In support of this notion, SARS-CoV-2 infection fails to limit STAT1 phosphorylation, unlike in SARS-CoV-1 infection (Lokugamage et al., 2020).
SARS-CoV-2 can evade by inhibiting type I/III IFN production from infected cells (Blanco-Melo et al., 2020). In fact, patients with severe COVID-19 exhibit remarkably impaired IFN-I signatures as compared to mild or moderate cases (Hadjadj et al., 2020). CoV-mediated antagonism of innate immunity begins with evasion of PRR sensing. CoVs can avoid PRR activation via inhibiting recognition (Bouvet et al., 2010; Deng et al., 2017; Knoops et al., 2008). Viral RNA is guanosine-capped and methylated at the 5 ends (Bouvet et al., 2010; Konstantin A. Ivanov et al., 2004), thereby resembling host messenger RNA (mRNA) to promote translation, prevent degradation, and evade RIG-I like Receptor (RLR) sensing (Deng et al., 2017).
Although no study has reported the precise functions of SARS-CoV-2 proteins, proteomic studies have demonstrated interactions between viral proteins and PRRs. SARS-CoV-1 and SARS-CoV-2 ORF9b indirectly suppresses mitochondrial antiviral signaling protein (MAVS) via its association with mitochondrial membrane (Tom)70 (Gordon et al., 2020).