Neutrophil Extracellular Traps Capturing SARS-CoV-2 in the Lung Tissue (Alveoli and Parenchyma) Cause Microthrombi - A Strategy to Eliminate SARS-CoV-2 From the Circulation as Degraded Fibrin Clots.

BACKGROUND

It has been thought that neutrophil extracellular traps (NETs) and thrombosis exacerbate COVID-19, but, on the other hand, NETs are an important player in innate immunity. The precise roles of NETs and thrombosis in the course of COVID-19 have not been fully elucidated.

METHODS AND RESULTS

The roles were investigated in the literature and a new theory was formulated. When neutrophils encounter SARS-CoV-2 in the lung tissue, they undergo NETosis and capture the virus. This capture is triggered by electrostatic interaction between histones in NETs and SARS-CoV-2; histones are highly positively charged, and viruses, including SARS-CoV-2, have a net negative charge under physiological pH. NETs that capture SARS-CoV-2 fall into alveolar capillaries through the collapsed endothelium to spare the lung tissue from the toxicity of NETs. NETs in the microvessels cause microthrombosis; positively charged histones induce the aggregation of negatively charged platelets, which leads to microthrombi. Microthrombi engulfing SARS-CoV-2 are consolidated into fibrin clots, which are eventually degraded by increased fibrinolysis and eliminated from the circulation.

CONCLUSIONS

This novel theory suggests that NETosis and microthrombosis are phenomena inevitably elicited in COVID-19, and in combination they are a system newly termed "NETombosis". Undegraded fibrin clots remaining in the microcirculation may be the cause of the sequelae, because they cause long-lasting circulatory failure in various organs.