Biophysical mechanisms of SARS-CoV-2-induced surfactant inhibition

Surfactant replacement has been studied as a supportive therapy for managing COVID-19-induced acute respiratory distress syndrome. The clinical applications require biophysical understanding of the molecular mechanisms behind SARS-CoV-2-induced surfactant inhibition. Although SARS-CoV-2 is known to attack alveolar type II epithelial cells, it is unknown whether the virus can directly interact with the pulmonary surfactant film adsorbed at the alveolar surface. The virus utilizes its spike (S) protein, consisting of two functional subunits (S1 and S2), to bind to the host cell membrane and mediate subsequent membrane fusion. We hypothesize that these two subunits may differentially interact with pulmonary surfactant, resulting in distinct effects on surfactant inhibition. The biophysical impact of recombinant S1 and S2 subunit proteins on a bovine-extracted natural pulmonary surfactant film was investigated with combined constrained drop surfactometry and atomic force microscopy. Our findings revealed that the S2 subunit, in contrast to the S1 subunit, selectively induces surfactant inhibition, evidenced by its capacity in reducing dynamic surface activity and causing domain fusion in surfactant monolayers. These results contribute novel insights into the biophysical mechanisms underlying surfactant inhibition in SARS-CoV-2-induced acute respiratory distress syndrome and may hold translational implications for advancing surfactant therapy to manage COVID-19.