Stealth replication of SARS-CoV-2 Omicron in the nasal epithelium at physiological temperature

The COVID-19 pandemic was marked by successive waves of SARS-CoV-2 variants with distinct properties. The Omicron variant that emerged in late 2021 showed a major antigenic shift and rapidly spread worldwide. Since then, Omicron-derived variants have maintained their global dominance, for reasons that remain incompletely understood. We report that the original Omicron variant BA.1 evolved several traits that converged in facilitating viral spread. First, Omicron displayed an early replicative advantage over previous variants when grown in a reconstructed nasal epithelium model based on primary human cells. The increase in Omicron replication was more marked at the 33°C temperature characteristic of human nasal passages, resulting in a physiologically relevant advantage. Omicron also caused a decrease in epithelial integrity, as measured by transepithelial electrical resistance and caspase-3 activation. Furthermore, Omicron caused a more marked loss of motile cilia at 33°C than other variants, suggesting a capacity to impair mucociliary clearance. RNAseq analysis showed that Omicron induced a broad transcriptional downregulation of ciliary genes but only a limited upregulation of host innate defense genes at 33°C. The lower production of type I and type III interferons in epithelia infected by Omicron compared to those infected by the Delta variant, at 33°C as well as 37°C, confirmed the increased capacity of Omicron to evade the innate antiviral response. Thus, Omicron combined replication speed, motile cilia impairment, and limited induction of innate antiviral responses when propagated in reconstructed nasal epithelia at physiological temperature. Omicron has the capacity to propagate efficiently but stealthily in the upper respiratory tract, which likely contributed to the evolutionary success of this SARS-CoV-2 variant.