Toll-Like Receptors in COVID-19 Pathogenesis

Description:

Toll-like receptors (TLRs) are a group of trans-membrane pattern recognition receptors (PRRs) that play a crucial role in the recognition of pathogen associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). TLR, a member of innate immune receptor family is primarily important in the activation of innate immunity, cytokine genes regulation as well as in the initiation of adaptive immune responses. To date, 10 human TLRs have been identified that are widely distributed in both immune and other body cells.

Ligands binding to TLRs activate intracellular signaling cascades that lead to the production of pro-inflammatory cytokines, type I IFN and other mediators responsible for the activation of the immune response. Many cell membrane bound TLRs like TLR1, TLR2, TLR4 and TLR6 as well as endosomal TLRs (TLR3, TLR7,TLR8, and TLR9) are potentially important in COVID-19 infection.In COVID-19, TLRs recognize SARS-CoV-2 S-proteins, oxidized phospholipids (OXPLs) induced by SARS-CoV-2 infection, high mobility group box 1 (HMGB1), beta-defensin-3 peptide as well as viral single-stranded RNA as PAMPs/DAMPs. SARS-CoV-2 binds to different TLRs in addition to ACE2 which may trigger activation of TLR pathways. TLRs may be the main PRRs responsible for the induction of cytokine storm during COVID-19 pathogenesis. TLR activation via MyD88-dependent and TRIF-dependent pathways causes activation of NF-κB, IRF-3 and IRF-7, which culminate with a sharp release of innate pro-inflammatory cytokines (IL-1, IL-6, TNF-α) and type I IFN-α/β causing cytokine storm.

Toll-like receptors (TLRs) may be involved both in the failure of viral clearance during the initial stage as well as during severe COVID-19 complications that may lead to viral pneumonia, acute respiratory distress syndrome (ARDS) and respiratory failure. Targeting TLRs using pharmacological agents available for clinical testing can be an important therapeutic option in the fight against COVID-19 that is posing a great threat to the world in the current scenario.