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.

Causes of mortality from COVID-19 include respiratory failure, heart failure, and sepsis/multi-organ failure. TLR4 is an innate immune receptor on the cell surface that recognizes Pathogen Associated Molecular Patterns (PAMPs) including viral proteins and triggers the production of type I interferons and pro-inflammatory cytokines to combat infection. It is expressed on both immune cells and tissue-resident cells. ACE2, the reported entry receptor for SARS-CoV-2, is only present on ~1-2% of the cells in the lungs or has a low pulmonary expression, and recently the spike protein has been proposed to have the strongest protein-protein interaction with TLR4. Here we review and connect evidence for SARS-CoV-1 and SARS-CoV-2 having direct and indirect binding to TLR4, together with other viral precedents, which when combined shed light on the COVID-19 pathophysiological puzzle. We propose a model in which the SARS-CoV-2 spike glycoprotein binds TLR4 and activates TLR4 signalling to increase cell surface expression of ACE2 facilitating entrySARS-CoV-2 also destroys the type II alveolar cells that secrete pulmonary surfactants, which normally decrease the air/tissue surface tension and block TLR4 in the lungs thus promoting ARDS and inflammation. Furthermore, SARS-CoV-2 induced myocarditis and multiple-organ injury may be due to TLR4 activation, aberrant TLR4 signalling and hyperinflammation in COVID-19 patients. Therefore, TLR4 contributes significantly to the pathogenesis of SARS-CoV-2 and its over-activation causes a prolonged or excessive innate immune response. TLR4 appears to be a promising therapeutic target in COVID-19 and since TLR4 antagonists have been previously trialled in sepsis and in other antiviral contexts, we propose the clinical trial testing of TLR4 antagonists in the treatment of sever COVID-19. Also, ongoing clinical trials of pulmonary surfactants in COVID-19 hold promise since they also block TLR4.