Evolution of the SARS-CoV-2 spike protein in utilizing host transmembrane serine proteases
Aleksandra Milewska, Luis Fernando Cofas-Vargas, Adolfo B Poma, Krzysztof Pyrć
iScience, doi:10.1016/j.isci.2025.113318
SARS-CoV-2 entry into host cells depends on proteolytic activation of the spike protein by host proteases, a process shaped by spike mutations that influence viral specificity and infectivity. Using human airway epithelial models, this study investigated how different SARS-CoV-2 variants interact with host serine proteases. The Delta variant exhibited enhanced and stable binding to Hepsin through stronger ionic and hydrophobic interactions, promoting efficient spike activation and cell entry. In contrast, Omicron BA.1 showed weaker Hepsin binding and relied more on TMPRSS2 or cathepsins, depending on the cellular context. These findings reveal how variant-specific differences in protease usage are linked to spike protein mutations and cleavage site evolution. By illuminating the dynamic interplay between viral adaptation and host protease specificity, this work provides insights into mechanisms that influence viral transmission and immune evasion, with implications for developing targeted antiviral strategies and understanding the evolution of emerging SARS-CoV-2 variants.
AUTHOR CONTRIBUTIONS A.M., experimental design, carrying out experiments, data analysis, figure preparation, and manuscript writing. L.F.C.-V., carrying out experiments, data analysis, and figure preparation. A.B.P. and K.P., experimental design, obtaining funding, and manuscript writing.
DECLARATION OF INTERESTS The authors declare no conflict of interest.
STAR★METHODS Detailed methods are provided in the online version of this paper and include the following: , penicillin (100 U/mL; Thermo Fisher Scientific), and streptomycin (100 μg/mL; Thermo Fisher Scientific). A549 ACE2/TMPRSS2 cells were supplemented with blasticidin S (10 μg/mL, Sigma-Aldrich), and puromycin (0.5 μg/mL, Sigma-Aldrich) to maintain the ACE2+TMPRSS2+ population. Cells were cultured at 37 • C, 5% CO2, and 95% humidity. All cell lines were tested every two weeks for mycoplasma contamination either by in-house DAPI staining or LookOut® Mycoplasma PCR Detection Kit (Sigma-Aldrich).
Human epithelium (HAE) cultures Human airway epithelial cells (Epithelix SAS, Archamps, France) were maintained in BEGM medium. Before the test, cells were trypsinised and transferred to a permeable transwell insert supports (f = 6.5 mm). Cell differentiation was stimulated by medium additives. The removal of the media from the apical side was performed after the cells reached confluence. Cells were cultured for 3 to 5 weeks to form well-differentiated, pseudostratified mucociliary epithelia, as previously described.
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