SARS-CoV-2 subversion of innate immune responses
In addition to strategies to evade PPR recognition SARS-CoV-2 has also evolved strategies to inhibit steps in the pathway leading to type I/III IFN production. This may be especially relevant in the lungs where type IFN III (lambda) is considered to be more effective in controlling viral infections, and critically affected in COVID-19. Knowledge arising from the study of other coronaviruses, especially SARS-CoV and MERS has shown that many of the non-structural, structural and accessory proteins interfere with elements of the IFN pathway [Table 2, figure 2] essential for the development of effective immunity. IFN antagonism has been attributed to several of the structural, non-structural and accessory proteins that interfere with stimulator of interferon genes (STING)-TRAF3-TBK1 complex thereby blocking STING/TBK1/IKKε-induced type I IFN production, STAT-1/2 translocation to the nucleus, IRF3, NFκB signalling as well as interfering with the actions of the ISG products including IFITs [Table 2]. As examples, nsp1, 4 and 6, and ORF6 interfere with STAT-1/2 signalling (34–36,39,53) while nsp 10, 13 and 16 cap viral RNA (26,45–47,49) prevent recognition by RIG-I, MDA5 and IFITs. Nsp3 also acts by DUB proteins thereby preventing their activity such as RIG-I and other steps in the IFN pathways for which ubiquination is essential. CoV PLPro (nsp 3) also interrupts the stimulator of interferon genes STING.TRAF3.TBK1 complex thereby blocking STING/TBK1/IKKε-type I IFN production (40). As well as subversion of the IFN pathway, SARS-CoV ORF7a (also present in SARS-CoV-2) blocks the activity of tetherin also known as bone marrow stromal antigen 2 (BST2) (60). BST2 acts by tethering budding viruses to the cell membrane thus preventing its release from the cells, thus ORF7a removes this inhibition aiding the release of mature virions.
In summary, emerging evidence from SARS-CoV-2, and comparison with other SARS-Cov and MERS, reveals many strategies used to evade the innate immune response and subvert the interferon pathway. While this facilitates widespread viral replication increasing the viral load also promotes the viral cytopathic effects leading to tissue damage described below likely leads to exacerbation and hyperinflammation of the innate immune response once triggered.