Table 1.

Coronavirus antagonism upstream of interferon induction.

Coronavirus	Mechanism of evasion upstream of IFN signaling	References
SARS-CoV	Viral protein PLP (NSP3) inhibits IFNs production by blocking the nuclear translocation and phosphorylation of IRF3. PLP adversely controls the antiviral immune response by inhibiting the STING signaling.	[84,85,86]
	Viral NP, ORF3b, and ORF6 prevent the TRIM25 activation of RIG-I and inhibit the transcription of ISGs. Viral NP inhibits the IRF3 function.	[87,88,89,90]
	ORF6 antagonizes the STAT1 function.	[91]
	Viral protein NSP14 mimics the 5ꞌcap structure on the viral RNA by its guanine -N7-methyltransferase activity.	[92]
	Viral protein NSP15 acts on negative-sense viral RNA by cleaving its 50-polyuridines.	[93]
	ORF3a induces the degradation of IFNAR1.	[94]
	Viral EP, ORF3a, and ORF8b induce the pro-inflammatory cytokines through NF‐κB activation after triggering the NLRP3 inflammasome.	[95,96,97,98]
SARS-CoV-2	ORF3b suppresses the induction of type I IFNs by acting on IRF3 or MAVS.	[99]
	Viral protein NSP15 inhibits the induction of IFNs production by interacting and closing the signaling RIG-I/MAVS and IRF3.	[55]
	Viral protein NSP15 interacts with RNF41, an activator of IRF3 and TBK1. The viral protein NSP13 interacts with the signaling transitional TBK1 that mediates the production of IRF3. NSP13 antagonizes the NF-kB pathway.	[55]
	Viral protein NSP10 induces the production of cytokine storm by facilitating the IL-8 induction after interacting with NKRF.	[100]
	ORF6 inhibits nuclear export of host mRNA by targeting the NUP98-RAE1 complex.	[55]
	ORF9c antagonizes the NF-kB pathway.	[55]
MERS-CoV	ORF, 4a, 4b, and 5 inhibit the nuclear translocation of IRF3 and induce the suppression of IFNs production.	[101]
	Viral protein NS4a is a type I and type III IFNs antagonist, which itself binds to the dsRNA, impedes PKR activation, and inhibits the PACT, an activator of RLRs.	[102,103,104]
	Viral protein NS4b prevents the host RNase L activation, another activator of RLRs.	[105]
	ORF4b protein inhibits the type I IFN production through nuclear and cytoplasmic targets. ORF4b impedes the innate immune response by inhibiting the NF-kB nuclear transport.	[106,107]
HCoVs	Viral proteins NSP10 and NSP16 protect the viral RNA from MDA5 recognition by modifying the 5ꞌ cap structure with its 2ꞌ-0-methyltransferase activity.	[108,109]
	Viral protein NSP1 inhibits the phosphorylation of STAT1 and host mRNA translation by binding to 40S ribosomal subunit.	[87,88,110,111,112,113]
	ORF9b (except for MERS-CoV) interacts indirectly with the RIG-I/MAVS signaling adapter via its association with Tom70, suggesting a preserved mechanism of IFNs escape. ORF9b interacts with the IRF3 signaling pathway.	[55,114]
	Viral MP inhibits the TBK1 signaling and nuclear translocation of IRF3. Viral MP interacts with the innate receptors and signaling molecules to impound them in the cytoplasmic compartments.	[101,115]
	ORF6 (except for MERS-CoV) inhibits the MAVS, TBK1, and IRF3.	[116]

NSP, nonstructural protein; IRF, IFNs regulatory factor; STAT1, signal transducer and activator of transcription 1; ORF, open reading frame; PLP, papain-like protease; ISG, IFN-stimulated genes; TRIM 25, tripartite motif-containing 25; NP, nucleocapsid protein; MP, matrix protein; EP, envelope protein; RIG-I, retinoic acid-inducible gene I; MAVS, mitochondrial antiviral signaling protein; TBK1, tank-binding kinase-1; Tom70, translocase of the mitochondrial outer membrane 70; RNF41, ring finger protein 41; NKRF, NF-Kβ repressing factor; PKR, protein kinase R; RLRs, RIG-I-like receptors; STING, stimulator of interferon genes; PACT, protein activator; RAE1, ribonucleic acid export 1; NUP98, Nucleoporin 98.