COVID-19 Pathology Sheds Further Light on Balance between Neutrophil Proteases and Their Inhibitors

Excessive neutrophil influx and activation in lungs during infections, such as manifest during the ongoing SARS CoV-2 pandemic, have brought neutrophil extracellular traps (NETs) and the concomitant release of granule contents that damage surrounding tissues into sharp focus. Neutrophil proteases, which are known to participate in NET release, also enable the binding of the viral spike protein to cellular receptors and assist in the spread of infection. Blood and tissue fluids normally also contain liver-derived protease inhibitors that balance the activity of proteases. Interestingly, neutrophils themselves also express the protease inhibitor alpha-1-antitrypsin (AAT), the product of the SERPINA-1 gene, and store it in neutrophil cytoplasmic granules. The absence of AAT or mutations in the SERPINA-1 gene promotes lung remodeling and fibrosis in diseases such as chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS) and increases the risk of allergic responses. Recent observations point to the fact that reduced activity of AAT presents a major susceptibility factor for severe COVID-19. Here, we focus attention on the mechanism of neutrophil elastase (NE) in NET release and its inhibition by AAT as an additional factor that may determine the severity of COVID-19.

Automated summary

Excessive neutrophil influx and activation during respiratory infections, such as the ongoing SARS CoV-2 pandemic, lead to the release of neutrophil extracellular traps (NETs) and granule contents that can damage lung tissues. Proteases released by neutrophils not only participate in NET release, but also facilitate viral spike protein binding and infection spread. The absence of the protease inhibitor alpha-1-antitrypsin (AAT) or mutations in the SERPINA-1 gene, which encodes AAT, contribute to lung remodeling, fibrosis, and increased susceptibility to severe COVID-19.