Fig. 5

Immune signaling pathway of infected cells. Transmembrane protease serine 2 primes the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein. The activated S protein binds to angiotensin converting enzyme-2 (ACE2), resulting in membrane fusion. Thereafter, SARS-CoV-2 RNA chain invades the cells and replicates. The binding of ACE2 to the S protein is blocked, resulting in mitochondrial damage and mitochondrial DNA (mtDNA) leakage. S proteins can activate Toll-like receptor (TLR) 2 and 4 on the cell surface, whereas ssRNA and CpGDNA can activate endosomal TLR7/8 and TLR9, thereby activating the nuclear factor kappa light chain enhancer of activated B cells (NF-κB) pathway and TRAF6 by MyD88 dependent pathway. TLR3 binds to dsRNA and activate TRAF3 and TRAF6 by MyD88 independent pathway, thereby activating interferon regulating factor (IRF) 3 and 7. MtDNA activates the cGAS-STING pathway, which in turn activates the NF-κB pathway and IRF3. NF- κB pathway regulates the expression of various cytokines and chemokines, whereas IRF3 and IRF7 regulate the expression of type I interferon. Secreted tissue-necrosis factor-alpha (TNF- α) binding to TNF receptor cell surface activates the TNF pathway and enhances the NF- κB pathway. Interferon-1 and Interleukin-6 bind to responsive receptors to activate the JAK/STAT pathway, thereby promoting the secretion of proinflammatory factors. SARS-CoV-2 accessory proteins participate in the regulation of cellular immune signal transduction. Non-structural protein (NSP)-5 and ORF7a can activate NF- κB pathway; 3CL, ORF3a, ORF9b, and ORF10 can inhibit the activation of SRING protein, whereas ORF9b and NSP7 can inhibit the activation of TRAF3