ABSTRACT
The ongoing SARS-CoV-2 pandemic has been marked with emerging viral variants, some of which were designated as variants of concern (VOCs) due to their selection and rapid circulation in the human population. Here we elucidate functional features of each VOC in patient-derived primary nasal cultures grown at air-liquid-interface (ALI) to model upper-respiratory infection, and human lung epithelial cell lines to model lung infection. All VOCs replicated to higher titers than the ancestral virus, and Omicron reached the higher titer in the upper-respiratory system in both nasal cells and parallel human studies. Delta was most adept at cell-to-cell spread and the most cytopathic to nasal cells by compromising cell-barrier integrity and ciliary beating. All VOCs overcame dsRNA-activated cellular responses including interferon signaling, oligoadenylate ribonuclease L (OAS-RNase L) degradation and protein kinase R (PKR) activation. Our findings highlight the functional differences among VOCs and illuminate distinct mechanisms of pathogenesis in infected individuals.