Comparison of SARS-CoV-2 variants of concern in primary human nasal cultures demonstrates Delta as most cytopathic and Omicron as fastest replicating

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.

Interferon signaling in the nasal epithelium distinguishes among lethal and common cold respiratory viruses and is critical for viral clearance

“…Thus, we compared the ancestral SARS-CoV-2/WA-1 (used for all SARS-CoV-2 experiments previously described) with omicron BA.1 in this nasal cell model to determine if SARS-CoV-2 had evolved to exhibit features of common cold-associated viruses. Comparing the replication kinetics of SARS-CoV-2 WA-1 with omicron BA.1 at 33°C confirmed a number of reports which have found that omicron replicates more rapidly in nasal cultures 64,65 . Omicron BA.1 replication reached peak titers by 48 hpi, whereas SARS-CoV-2 WA-1 titers peaked at 144 hpi ( Figure 7A ).…”

“…To assess the degree of IFN signaling pathway induction during omicron infection, we performed western blot analysis using protein extracted from SARS-CoV-2 WA-1- or omicron BA.1-infected nasal cells, which revealed an increase in STAT1 phosphorylation as well as ISG protein abundances during omicron BA.1 infection relative to SARS-CoV-2 WA-1 ( Figure 7B ) 65 . Finally, since clearance of common cold-associated viruses was associated with IFN responses, we compared the sensitivity of omicron BA.1 with the earlier isolate, SARS-CoV-2 WA-1 ( Figure 7C ).…”