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.
Highlights
The SARS-CoV-2 virus has caused a worldwide pandemic in 2020, infecting millions of people and leading to a global health crisis [1]
(1) evidence that TLR4 has the strongest protein-protein interaction with the spike glycoprotein of SARS-CoV-2 compared to other TLRs [30], together with (2) evidence that SARS-COV-2 strongly induces interferonstimulated gene (ISG) expression in an immunopathogenic context in the respiratory tract [31]; (3) evidence that ISG activation results in increased expression of angiotensin converting enzyme 2 (ACE2) [32] and (4) evidence that pulmonary surfactants in the lung prevent viral infection by blocking TLR4 [33] suggest a possible mechanism in which the virus may be binding to and activating TLR4 to increase expression of ACE2 which promotes viral entry
Reviews have proposed direct viral entry via spike protein interacting with the specific ACE2 receptors on cardiomyocytes and thereby toxicity in host cells [43, 51], one commentary regarded it as a “potential mechanism” in the presence of limited data, given that ACE2 “is highly expressed in the heart and lungs” [49, 52]. scRNAseq data showed more than 7.5% myocardial cells were positive for ACE2 expression putting the heart at risk in the presence of viraemia [10]
Summary
The SARS-CoV-2 virus has caused a worldwide pandemic in 2020, infecting millions of people and leading to a global health crisis [1]. (1) evidence that TLR4 has the strongest protein-protein interaction with the spike glycoprotein of SARS-CoV-2 compared to other TLRs [30], together with (2) evidence that SARS-COV-2 strongly induces interferonstimulated gene (ISG) expression in an immunopathogenic context in the respiratory tract [31]; (3) evidence that ISG activation results in increased expression of ACE2 [32] and (4) evidence that pulmonary surfactants in the lung prevent viral infection by blocking TLR4 [33] suggest a possible mechanism in which the virus may be binding to and activating TLR4 to increase expression of ACE2 which promotes viral entry This is supported by the fact that ISGs are downstream of TLR4-interferon signalling, thereby linking these phenomena. This review highlights a potential role of TLR4 in SARS-CoV-2 entry mechanisms and the subsequent severe inflammatory complications with a focus on injury to the lungs and heart, since they are the major causes of mortality from COVID-19
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