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.