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

Figure 1

Graphical abstract. Note that less pulmonary surfactant secretion leads to exposed TLR4 receptors on alveolar cells. HMGB1 released from lysed cells can also activate TLR4 causing excessive inflammation and fibrosis. The same model applies to a cardiac cell, except that there would be no pulmonary surfactants, and instead of the outside air, it would be the extracellular matrix. In the heart, TLR4 activation by the SARS-CoV-2 virus and/or DAMPs released from infected, necrotic cells or even upregulated at sites of injury may also cause abnormal signalling towards the canonical proinflammatory pathway rather than the alternative anti-inflammatory pathway. This would cause viral myocarditis. TLR4 activation also decreases the contractility of cardiomyocytes. In addition, SARS-CoV-2 may activate TLR4 to increase PI3K/Akt signalling in infected cells, preventing apoptosis and thus increasing time for viral replication. Aberrant inflammatory signalling could also be extended to other tissues expressing TLR4, such as the skin and kidney, where the virus would therefore cause multiple-organ injury.