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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

Mohamed M. Aboudounya, Richard J. Heads

Mediators of Inflammation · 2021 · Review · CC BY

doi:10.1155/2021/8874339

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 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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Toll-like receptor 4 in acute viral infection: Too much of a good thing · 2018
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111.
Zhang Y., Rassa J. C., deObaldia M. E., Albritton L. M., Ross S. R. Identification of the receptor binding domain of the mouse mammary tumor virus envelope protein. Journal of Virology. 2003;77(19):10468-10478.
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112.
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MyD88 Is Required for Protection from Lethal Infection with a Mouse-Adapted SARS-CoV · 2008
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122.
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Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19? · 2020
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127.
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128.
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130.
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Type III interferons disrupt the lung epithelial barrier upon viral recognition · 2020
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132.
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140.
Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients · 2020
No notice
141.
Make Yourself at Home: Viral Hijacking of the PI3K/Akt Signaling Pathway · 2013
No notice
142.
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144.
Ramamoorthy S., Cidlowski J. A. Corticosteroids: mechanisms of action in health and disease. Rheumatic Diseases Clinics of North America. 2016;42(1):15-31.
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Polin R. A., Carlo W. A., Committee on Fetus and Newborn, American Academy of Pediatrics. Surfactant replacement therapy for preterm and term neonates with respiratory distress. Pediatrics. 2014;133(1):156-163.
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151.
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153.
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155.
Ehrentraut H., Weber C., Ehrentraut S., et al. The toll-like receptor 4-antagonist eritoran reduces murine cardiac hypertrophy. European Journal of Heart Failure. 2011;13(6):602-610.
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Not in our library10.3892/mmr.2017.7825

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