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

• Subject Area: Immunology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 114933180

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.

• DFG Programme: CRC/Transregios
• Subproject of: TRR 84: Innate Immunity of the Lung: Mechanisms of Pathogen Attack and Host Defence in Pneumonia
• Applicant Institution: shared FU Berlin and HU Berlin through:; Charité - Universitätsmedizin Berlin
• Project Heads: Professor Dr. Wolfgang Kübler; Professor Dr. Norbert Suttorp; Professor Dr. Martin Witzenrath