Fig. 3.

Schematic illustration of the innate immune response to human coronavirus infection. The HCoVs infect the host cell through interaction between its spike protein (S) and the cell receptor, ACE2. Upon viral RNA recognition, the PRRs activate the innate cellular response reactions that normally lead to the production of pro-inflammatory cytokines and IFNs through NF-kB and IRF3/IRF7 (A). IFNs, secreted in an autocrine and paracrine behavior, induce the expression of ISGs via the JAK-STAT signaling pathway involved in antiviral response (B). Some viral proteins such as SARS-CoV’s NSP1, PLP, NSP10, NSP13, NSP14, NSP15, ORF3b, and ORF9b proteins and the MERS-CoV’s NS4a, NS4b, ORF4a, ORF4b, and ORF5 proteins inhibit this natural response at several levels. See Table 1 for detailed mechanisms at each level.

HCoVs, human coronavirus; PRRs, pattern-recognition receptors; TLRs, toll-like receptors; RIG-I, retinoic acid-inducible gene I; MAVS, mitochondrial antiviral signaling protein; NSP, non-structural protein; IRF, IFNs regulatory factor; STAT, signal transducer and activator of transcription; ORF, open reading frame; PLP, papain-like protease; ISG, IFN-stimulated genes; N, nucleocapsid protein; M, matrix protein; E, envelope protein; TBK1, TANK-binding kinase-1; MyD88, myeloid differentiation primary response 88; TRIF, TIR domain-containing adapter-inducing IFN-β; PKR, protein kinase R; RIG-I, retinoic acid-inducible gene 1; RLRs, RIG-I-like receptors; STING, stimulator of interferon genes; MDA-5, melanoma differentiation-associated protein 5; IkB, inhibitor of nuclear factor kB; IKK-ε, IκB kinase-ε; NLRP3, NOD-like receptor family pyrin domain containing 3; IFNAR, interferon alpha and beta receptor; IFNLR, interferon lambda receptor; TRIMs, tripartate motif proteins; P, phosphate; GBPs, guanylate binding proteins; OASs, oligo adenylate synthases; NOS2, nitric oxide synthase 2; IFITMs, IFN-induced transmembrane proteins.