Fig. 2.

ACE-2-TMPRSS2-mediated SARS-CoV-2 cell entry and type 1 interferon pathway. SARS-CoV-2-associated molecules are recognized by a wide range of PRRs located in different compartments, including TLR2, 4 and 6 on the plasma membrane, TLR3, 7 and 8 in endosomes, and RIG-1 and MDA-5 in the cytoplasm, each with its respective ligands. Ligand binding causes TLRs to dimerize and instigate the downstream signaling pathways in an MyD88-dependent or TRIF-dependent manner. Activation of TLR2, 4, 7, and 8 recruits the canonical adaptor protein MyD88, which sequentially mobilizes the IRAK complex, TRAF6, and TAK1. TAK1 is then capable of initiating the IKK-NFκB and the MAPK-AP1 pathways, stimulating production of various proinflammatory cytokines. In addition, activation of TLR7 or TLR8 also triggers IRAK, TRAF6, TRAF3, and IKKα-dependent phosphorylation and thus activation of IRF7. Contrarily, TRAF3 may be activated by TRIF recruitment following TLR3 and TLR4 activation, or MAVS recruitment secondary to RIG-1 or MDA5 activation. TRAF3 in turn gives rise to TBK1 and IKKε activation that potentiates IRF3. Both IRF3 and IRF7 act as transcription factors that promote T1IFN gene expression. T1IFNs bind to the heterodimeric IFNAR1/IFNAR2 receptor complex, which triggers the receptor-associated kinases TYK2 and JAK1 to phosphorylate STAT1 and STAT2 proteins. The phosphorylated STAT1 and STAT2 combine with IRF9 to form the ISGF3, which binds to IRSE in the nucleus to upregulate transcription of ISGs, exerting multitudinous antiviral effects. PPRs pattern recognition receptors, ACE2 angiotensin-converting enzyme 2, TMPRSS2 transmembrane serine protease 2, (+)/(–)ssRNA positive-/negative-sense single-stranded ribonucleic acid, S spike protein, N nucleocapsid protein, M membrane protein, E envelop protein, Nsps non-structural proteins, dsRNA double-stranded ribonucleic acid, TLR toll-like receptor, RIG-1 retinoic acid-inducible gene I, MDA5 melanoma differentiation-associated protein 5, MyD88 myeloid differentiation primary response factor 88, IRAKs interleukin-1 receptor-associated kinases, TRIF toll-interleukin-1 receptor-domain-containing adaptor-inducing interferon-‍β, MAVS mitochondrial antiviral signaling protein, TRAF tumor necrosis factor receptor-associated factor, TAK1 transforming growth factor-β activated kinase 1, IKK inhibitor of nuclear factor-κB (IκB) kinase, TBK1 TANK-binding kinase 1, IRF interferon regulatory factor, NF-κB nuclear factor kappa B, MAPK mitogen-activated protein kinase, AP-1 activator protein 1, T1IFNs type 1 interferons, IFNAR interferon-alpha receptor, TYK2 tyrosine kinase 2, JAK1 Janus kinase, STAT signal transducer and activator of transcription, ISGF3 interferon-stimulated gene factor 3, ISRE interferon-sensitive response element