Protective effect of CFTR modulators on endothelial barrier failure in COVID-19 induced ARDS (C09*)

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Severe SARS-CoV-2 induced pneumonia causes injury of and increased leak across the lung endothelial barrier. We recently identified the Cl- channel cystic fibrosis transmembrane conductance regulator (CFTR) as critical regulator of endothelial barrier function. Specifically, we found that Streptococcus pneumoniae infection causes loss of CFTR protein and function that drives endothelial barrier failure but can be prevented by CFTR modulators. In pilot data, we demonstrate a similar loss of endothelial barrier function in severe COVID-19 that is again attenuated by CFTR modulators. As CFTR dysfunction in pulmonary artery smooth muscle cells, platelets, and neutrophils inhibits hypoxic pulmonary vasoconstriction, and causes platelet and neutrophil activation, loss of functional CFTR in COVID-19 may present a master switch that drives key features of the disease, and can be therapeutically targeted by CFTR modulators. Here, we will put this hypothesis to the test.