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

## TL;DR

The Omicron variant of SARS-CoV-2 replicates efficiently in nasal cells at body-like temperatures while evading immune detection, explaining its rapid global spread.

## Contribution

Discovery that Omicron's stealth replication in nasal epithelium at physiological temperature contributes to its dominance.

## Key findings

- Omicron replicates faster in nasal epithelium at 33°C compared to other variants.
- Omicron impairs mucociliary clearance and causes limited innate immune response at 33°C.
- Omicron induces reduced interferon production compared to Delta variant at both 33°C and 37°C.

## Abstract

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 human nasal epithelium model. The increase in Omicron replication was more marked at the physiologically relevant temperature of 33°C found in human nasal passages. 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. 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 nasal epithelia at physiological temperature. Omicron has the capacity to propagate rapidly but stealthily in the upper respiratory tract, which likely contributed to the evolutionary success of this SARS-CoV-2 variant.

The 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 the previous one. 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. Here, we compared the replication of SARS-CoV-2 variants in a human nasal epithelium model grown at 37°C and also at 33°C, a temperature that approximates that found in the nasal cavity. In this primary epithelial model, Omicron showed an early replicative advantage that was more marked at 33°C. However, Omicron triggered only a minimal antiviral interferon response at this temperature. Omicron could thus propagate rapidly while partly escaping the innate response at physiological nasal temperature, which helps account for the efficient dissemination of this variant worldwide.