FIGURE 2  Molecular and signaling pathway implicated in host cell antiviral response. (A) After the viral contents are released into the cytoplasm, the viral RNA is recognized by host cell NASs like RIG-I and MDA5. Counter-defense may be provided by the viral proteins, NSP14 and NSP16 to shield the viral RNA from sensing by the NASs. However, if successfully recognized, RIG-I and MDA5 get activated and subsequently activate the centrally placed MAVS located on mitochondria. MAVS acts as a molecular adaptor that further recruits TRAF2/3/5/6. Association of the type of TRAF with MAVS is suggested to determine the type of downstream signaling, i.e., IRF3/7 and/or NF-κB. At the MAVS junction, the association of TRAF5/6 with TRADD, FADD, and RIPK1 activates NF-κB. Whereas, binding of MAVS with STING activates TBK1 and IKKε by interacting with TRAF2/3, which eventually results in the activation of IRF3 and IRF7 (Chen et al., 2014). Activated IRF3, IRF7, and NF-κB translocate to the nucleus and induce the expression of IFN genes. (B) The transcribed IFNs act on the respective IFN receptors (IFNRs) present on the host cells as well as on other innate immune cells, thus signaling in a both autocrine and paracrine manner. Signaling via IFNRs activates the JAK/STAT signaling pathway and subsequently induces the expression of ISGs. These molecular events were recently reviewed (Rehwinkel and Gack, 2020). ISGs transcribed will eventually inhibit viral propagation. However, SARS-CoV and likely SARS-CoV-2 have developed counter-defense mechanisms to interfere at various steps in the NAS signaling pathway. NSP4a inhibits TRIM25, which is required for RIG-I activation. N protein inhibits MDA5, NSP14 inhibits MAVS, ORF9b inhibits RIG-I/MDA5 activation complex, M protein interferes with TANK, IKKε, and TBK1 signaling, and PLpro inhibits various RIG-I, MDA5, and MAVs downstream signaling steps. SARS-CoV-2 proteins acting at various steps in blocking NAS and IFN signaling are shown in the red box. NAS, Nucleic acid sensors; RIG-I, Retinoic acid-inducible gene I; MDA5, melanoma differentiation-associated protein 5; TRAF, TNF receptor-associated factor; STING, ER-associated stimulator of interferon genes; FADD, FAS-associated death domain protein; IRF, Interferon regulatory factor (IRF3/7); TRADD, TNFR1-associated death domain protein; IKKε, IκB kinase-ε; RIPK1, Receptor-interacting protein 1; TANK, TRAF family member-associated NF-kappa-B activator; TBK1, TANK-binding kinase 1; ISG, Interferon stimulatory gene; TRIM25, Tripartite motif-containing protein 25.