S142 Nasal cells from older adults exhibit early pro-fibrotic responses to SARS-CoV-2, which facilitates viral replication and spread

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Introduction Older adults (>75y) infected with SARS-CoV-2 have a heightened risk of developing severe COVID-19 and mortality, compared to younger age groups. In this study, we investigated how the nasal epithelial cell (NEC) landscape and functional responses of NECs, the initial site of SARS-CoV-2 infection, contribute to age-associated disease severity. Methods NECs from different age groups including older adult (>70 years) were cultured at air-liquid interface and infected with SARS-CoV-2. Single-cell RNA sequencing (scRNA-seq), supported by functional assays, immunofluorescence microscopy, and transmission electron microscopy (TEM) were used to profile the age-associated nasal epithelial cell response to infection. Results Infectious virus load was x1000 fold higher (p=0.04) in older adult NECs, with a mean viral titre of 1.64×10^7 pfu/well (1.71×10^4 pfu/well in paediatrics). This corresponded with emergence of a ‘Basaloid-like 2’ cell, previously characterised in pulmonary fibrosis patients and associated with aberrant wound healing pathways. TEM revealed increased epithelial damage and decreased epithelial integrity, evidenced by significant epithelial thinning and cell shedding (p<0.03, n=7). Stimulation of Basaloid-like cell marker expression through wounding increased the viral load in infected NECs from younger age groups (mean ± s.d. 4.09±3.61% to 9.69±9.04% dsRNA+ cells; p=0.03) particularly around the wound site. Analysis of 8 in vivo COVID-19 patient datasets validated these findings, with the greatest proportion of Basaloid-like 2 cells found in older adult COVID-19 patients. Conclusions Infected older adult NECs exhibit a bias towards a pro-fibrotic and remodelling response which facilitates further viral replication and spread. These findings highlight critical age-dependent differences in nasal epithelial cell-intrinsic immunity against respiratory infection.

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