ABSTRACT
Pulmonary surfactant has been attempted as a supportive therapy to treat COVID-19. Although it is mechanistically accepted that the fusion peptide in the S2 subunit of the S protein plays a predominant role in mediating viral fusion with the host cell membrane, it is still unknown how the S2 subunit interacts with the natural surfactant film. Using combined bio-physicochemical assays and atomic force microscopy imaging, it was found that the S2 subunit inhibited the biophysical properties of the surfactant and induced microdomain fusion in the surfactant monolayer. The surfactant inhibition has been attributed to membrane fluidization caused by insertion of the S2 subunit mediated by its fusion peptide. These findings may provide novel insight into the understanding of bio-physicochemical mechanisms responsible for surfactant interactions with SARS-CoV-2 and may have translational implications in the further development of surfactant replacement therapy for COVID-19 patients.