Article ; Online: 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.
2021 Volume 2021, Page(s) 8874339
Abstract: Causes of mortality from COVID-19 include respiratory failure, heart failure, and sepsis/multiorgan failure. TLR4 is an innate immune receptor on the cell surface that recognizes pathogen-associated molecular patterns (PAMPs) including viral proteins and ...
| Abstract | Causes of mortality from COVID-19 include respiratory failure, heart failure, and sepsis/multiorgan 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 proinflammatory 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 entry. SARS-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 overactivation 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 severe COVID-19. Also, ongoing clinical trials of pulmonary surfactants in COVID-19 hold promise since they also block TLR4. |
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| MeSH term(s) | Angiotensin-Converting Enzyme 2/metabolism ; Antiviral Agents/therapeutic use ; COVID-19/immunology ; Cell Proliferation ; Gene Expression Regulation ; Humans ; Immunity, Innate ; Inflammation ; Interferon Type I/metabolism ; Lung/metabolism ; Myocardium/metabolism ; Protein Binding ; Severe acute respiratory syndrome-related coronavirus ; SARS-CoV-2 ; Signal Transduction ; Spike Glycoprotein, Coronavirus/metabolism ; Surface-Active Agents ; Toll-Like Receptor 4/metabolism |
| Chemical Substances | Antiviral Agents ; Interferon Type I ; Spike Glycoprotein, Coronavirus ; Surface-Active Agents ; TLR4 protein, human ; Toll-Like Receptor 4 ; spike glycoprotein, SARS-CoV ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) |
| Language | English |
| Publishing date | 2021-01-14 |
| Publishing country | United States |
| Document type | Journal Article ; Review |
| ZDB-ID | 1137605-3 |
| ISSN | 1466-1861 ; 0962-9351 |
| ISSN (online) | 1466-1861 |
| ISSN | 0962-9351 |
| DOI | 10.1155/2021/8874339 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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