Figure 3.

The Interferon type I and III canonical signaling pathway. (1) Type I and III IFNs (e.g., IFN-α, IFN-β, IFN-λ) released from virus-infected cells bind to their receptors (e.g., IFNA/LR) on neighboring cells, leading to the dimerization of receptors and activation of JAK1 and TYK2. (2) The activated JAK1 and TYK2 phosphorylate the tyrosine residue of the IFN receptor which recruits various members of the STAT family as STAT 1 and STAT2. Also, JAK1 and TYK2 add phosphorus to recruit STATs and activate them. (3) Following separation from the receptor, STAT1/STAT2 dimer interacts with IRF9. (4) The STAT1/STAT2/IRF9 complex moves to the nucleus. (5) Placement of the complex on its promoter on the gene leads to the robust expression of many classical IFN-stimulated genes (ISGs, such as ISG15, MxA, IFITM, etc.), which exert an antiviral role to restrict viral replication and spreading (109). SARS-CoV-2 inhibits IFN production and response through a variety of methods. As a result, target cells close to the original infection fail to receive essential and protective IFN signals, allowing the virus to propagate. The ORF3a can inhibit type III IFN receptors. The structural proteins of SARS-CoV-2, N, and M, and nonstructural proteins such as NSP1, NSP6, NSP13, ORF3a, and ORF7b quench IFN signaling by inhibition of STAT1 phosphorylation. (c) The phosphorylation of STAT2 in COVID-19 is repressed by N, NSP6, NSP13, ORF7a, and ORF7b proteins. (d) The translocation of the STAT1/STAT2/IRF9 into the nucleus is inhibited by N and ORF6 proteins which attenuate the transcription of the interferon-stimulated gene (13, 110, 111). IFN, Interferon; ISG, Interferon Stimulated Gene; STAT, Signal Transducer and activator of Transcription; IRF9, Interferon Regulatory Factor 9; TYK2, Tyrosine Kinase 2; JAK, Janus Kinase; MxA, Myxovirus Resistance Gene A; IFITM, Interferon Induced Transmembrane; OFR, Open Reading Frame; NSP, None Structural Protein.