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. 2021 Jul 24;158:105105. doi: 10.1016/j.micpath.2021.105105

Fig. 2.

Fig. 2

A proposed model of host innate immunity induced by PAMPs. (A) The ssRNA enters the AEC and is recognized by intracellular receptors such as RLRs eventually transforming to an active form. The activated RIG-1 undergoes ubiquitination by E3 ligases and the CARD domain of ubiquitinated RIG-I interacts with the CARD domain of MAVS. The MAVS activates TBK1 and NF-kB through TRAF3 and IKK complex. The TBK1 phosphorylates IRF 7 and IRF 3 thereby stimulating type I IFN production; On the other hand, NF kB induces pro-inflammatory cytokine production. Aging is associated with the downregulation of proteins such as RLR, E3, and IRFs which impairs type I IFN production. Furthermore, nsp 6, N protein, nsp 13, nsp 14 and ORF 6 impair type I IFN production by inhibiting viral RNA sensing, TBK1 phosphorylation, and IRF phosphorylation. Conversely, N protein directly interacts with NF-kB and promotes cytokine release. (B) The interferon binds the IFNAR induces STAT homodimerization and heterodimerization thereby promoting the expression of ISGs and anti-inflammatory cytokines. Intriguingly, nsp 1, nsp 6, N protein, and ORF 6 inhibit STAT 1/STAT 2 phosphorylation and nuclear translocation eventually impairing interferon signaling. AEC, airway epithelial cell; PAMPS, pathogen-associated molecular patterns; ssRNA, single-stranded RNA; RLRs, RIG-I like receptor; CARD, caspase activator, and recruitment domain; MAVS, mitochondrial antiviral signaling; TBK 1, TANK-binding kinase 1; TRAF3, TNF receptor-associated factor 3; IRF 3 & 7, interferon regulatory factor 3 and 7; IFNAR, interferon-alpha/beta receptor; Tyk1, tyrosine kinase 1; Jak 2, Janus kinase 2; STAT 1 & 2, signal transducer and activator of transcription 1 and 2; ISGs, interferon-stimulated genes; nsp, non-structural proteins; ORF, open reading frame proteins; N, SARS-CoV-2 N protein.