Figure 4.

Proposed toll-like receptor 1, 4, and 6 involvement in SARS-CoV-2 infection into host cells. In silico studies have demonstrated direct binding between TLR1, 4, and 6 and the S1 interface of SARS-CoV-2 S protein [2], indicating that it may be a novel TLR pattern recognition receptor. Additionally, circulating TLR activating danger-associated molecular patterns (DAMP) have been reported in COVID-19 patients [94,96,100,128,129,130,131,132,133]. Activation by SARS-CoV-2 S protein and DAMPs may drive TLR mediated inflammation (through myeloid differentiation factor-88- and toll/IL-1-domain-containing adapter-inducing interferon-beta (TRIF)-dependent pathways) in patients with COVID-19 [144], manifesting as chronic inflammation, cytokine storm, and severe outcomes [100]. As such, we postulate that receptor-dependent internalization of the S protein may provide novel viral entry points, causing systemic spread independent of ACE2. Abbreviations: activator protein-1, AP-1; extracellular signal-regulated kinase, ERK; granulocyte colony-stimulating factor, G-CSF; granulocyte-macrophage colony-stimulating factor, GM-CSF; k protein 70, HSP70; inhibitor of nuclear factor kappa-beta kinase subunit, IKK; inositol-requiring enzyme-1 alpha, IRE1$\alpha$; interferon regulatory factor, IRF; interferon stimulated response element, ISRE; interluikin-1 associated receptor kinase, IRAK; c-Jun N-terminal kinase, JNK; macrophage inflammatory protein-1 MIP-1; mitogen-activated protein kinase, MAPK; myeloid differentiation factor-88 adaptor-like, MAL; receptor interacting protein-1, RIP-1; surfactant protein, SP; TANK-binding kinase 1, TBK1; toll/interluikin-1 receptor domain-containing adapter protein, TIRAP; toll/interluikin-1 receptor domain-containing adaptor-inducing interferon-beta, TRIF; toll-like receptor, TLR; toll interacting protein, TOLLIP; transforming growth factor beta activated kinase, TAB; translocating chain-associated membrane protein, TRAM; tumor necrosis factor receptor-associated factor, TRAF.