bioRxiv2025
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{degrees}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{degrees}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{degrees}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{degrees}C as well as 37{degrees}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. AUTHOR SUMMARYThe COVID-19 pandemic was initially characterized by a rapid succession of viral variants that emerged independently of each other, with each of these variants outcompeting previous ones and rising to regional or global dominance. A major evolutionary shift occurred in late 2021, with the emergence of the highly divergent Omicron BA.1 variant. Since then, all the dominant SARS-CoV-2 variants have been derived from Omicron, for reasons that remain incompletely understood. In this study, we chose to compare the replication of SARS-CoV-2 variants in a human nasal epithelium model grown at 37{degrees}C but also at 33{degrees}C, a more physiological temperature that approximates that found in the nasal cavity. In this model, Omicron showed an early replicative advantage that was more marked at nasal physiological temperature. Omicron also markedly impaired the layer of motile cilia that normally contributes to the clearance of inhaled particles from the nasal mucosa. Even though it caused tissue damage, Omicron triggered only a minimal antiviral interferon response from epithelia grown at 33{degrees}C. Thus, Omicron has the capacity to propagate rapidly but stealthily in the nasal epithelium at physiological temperature, which helps account for the efficient dissemination of this variant worldwide.