COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry and Causing Hyperinflammation

Figure 2

Overview of the main TLR4 signalling pathways. TLR4 can be activated by LPS (classical PAMP), DAMPs, or viral PAMPs. LPS is also picked up by the LPS-binding protein (LBP) present in the blood and in extracellular fluid in tissues. LPS is transferred from LBP to the coreceptor CD14. Recognition by MD2 and TLR4 binding results in the nuclear induction of transcription factors NF-κB and AP-1 via the MyD88-dependent pathway involving IRAKs, TABs, TAK, MAP kinases, and IKK isoforms. This results in the transcription of proinflammatory cytokines and regulators of cell proliferation, survival, and differentiation. In fibroblasts, this pathway mediates myofibroblast differentiation and results in CTGF and collagen production [100], while the alternative pathway is endosomal and involves TRIF and TRAM complex formation at the TIR domain. The alternative pathway results in the expression of anti-inflammatory cytokines, interferons α and β regulated by interferon regulatory factor 3 (IRF3), in addition to some NF-κB nuclear translocation. “Cross-talk” activation between the two pathways is indicated by brown arrows. Adaptors and cascade proteins are usually in homodimers, like the TLR4 receptor [22], but were omitted here for simplicity.