The adult nasal mucosa is defined by distinct immune profiles that modulate in-vitro SARS-CoV-2 infection.

Background The nasal mucosa is the primary entry site for many respiratory viruses, and immune molecules present at the time of exposure may dictate if infection occurs. However, the baseline immune state in healthy adults – and how it influences susceptibility to viruses – remains poorly defined. Methods Levels of 16 immune molecules were measured in nasal secretions from two independent cohorts of healthy adults (total n = 166, Luminex). Participants were clustered based on normalized concentrations of immune analytes to identify profiles. An in vitro organotypic model of the nasal epithelium was used to examine the effect of immune profiles on SARS-CoV-2 infection: primary human nasal epithelial cells (n = 9 donors) were grown at air-liquid interface to induce mucociliary differentiation (42 days), treated with recombinant human cytokines (72 hours), and then challenged with wildtype SARS-CoV-2 Omicron BA.1 (24 hours). SARS-CoV-2 entry factor expression (post-cytokines, pre-challenge) and viral infection (N gene) were measured by qRT-PCR. Results In both cohorts, a unique cluster was observed, characterized by distinctly high levels of antiviral interferons – particularly IFN-λ3 – with comparatively low levels of inflammatory chemokines and cytokines. In contrast, individuals with high overall levels of inflammatory mediators had absent IFN-λ3. In vitro , pretreatment with IFN-λ3 and IFN-α2, but not with pro-inflammatory cytokines, significantly reduced SARS-CoV-2 replication in differentiated nasal epithelial cultures, despite upregulating ACE2 expression. Conclusions Healthy adults exhibit distinct nasal immune profiles, with an IFN-λ3–dominant, low-inflammatory state conferring resistance to SARS-CoV-2 in vitro. The nasal immune milieu may influence susceptibility to respiratory viruses and the efficacy of mucosally administered vaccines.