The emergence of goblet inflammatory or ITGB6hi nasal progenitor cells determines age-associated SARS-CoV-2 pathogenesis

Woodall, M.; Cujba, A.-M.; Worlock, K. B.; Case, K.-M.; Masonou, T.; Yoshida, M.; Polanski, K.; Huang, N.; Lindeboom, R. G.; Mamanova, L.; Bolt, L.; Richardson, L.; Ellis, S.; Palor, M.; Burgoyne, T.; Pinto, A.; Moulding, D. A.; McHugh, T. D.; Saleh, A.; Kilich, E.; Mehta, P.; O'Callaghan, C.; Zhou, J.; Barclay, W.; De Coppi, P.; Butler, C. R.; Vinette, H.; Roy, S.; Breuer, J.; Chambers, R. C.; Heywood, W. E.; Mills, K.; Hynds, R. E.; Teichmann, S. A.; Meyer, K. B.; Nikolic, M. Z.; Smith, C. M.

doi:10.1101/2023.01.16.524211

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bioRxiv · 10.1101/2023.01.16.524211

The emergence of goblet inflammatory or ITGB6hi nasal progenitor cells determines age-associated SARS-CoV-2 pathogenesis

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Abstract

Children infected with SARS-CoV-2 rarely progress to respiratory failure, but the risk of mortality in infected people over 85 years of age remains high, despite vaccination and improving treatment options. Here, we take a comprehensive, multidisciplinary approach to investigate differences in the cellular landscape and function of paediatric (<11y), adult (30- 50y) and elderly (>70y) nasal epithelial cells experimentally infected with SARS-CoV-2. Our data reveal that nasal epithelial cell subtypes show different tropism to SARS-CoV-2, correlating with age, ACE2 and TMPRSS2 expression. Ciliated cells are a viral replication centre across all age groups, but a distinct goblet inflammatory subtype emerges in infected paediatric cultures, identifiable by high expression of interferon stimulated genes and truncated viral genomes. In contrast, infected elderly cultures show a proportional increase in ITGB6hi progenitors, which facilitate viral spread and are associated with dysfunctional epithelial repair pathways. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/524211v2_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@dab12aorg.highwire.dtl.DTLVardef@1a57334org.highwire.dtl.DTLVardef@12e7983org.highwire.dtl.DTLVardef@2bbe6e_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Woodall, M., Cujba, A.-M., Worlock, K. B., Case, K.-M., Masonou, T., Yoshida, M., Polanski, K., Huang, N., Lindeboom, R. G., Mamanova, L., Bolt, L., Richardson, L., Ellis, S., Palor, M., Burgoyne, T., Pinto, A., Moulding, D. A., McHugh, T. D., Saleh, A., Kilich, E., Mehta, P., O'Callaghan, C., Zhou, J., Barclay, W., De Coppi, P., Butler, C. R., Vinette, H., Roy, S., Breuer, J., Chambers, R. C., Heywood, W. E., Mills, K., Hynds, R. E., Teichmann, S. A., Meyer, K. B., Nikolic, M. Z., Smith, C. M.. 2023-01-17. The emergence of goblet inflammatory or ITGB6hi nasal progenitor cells determines age-associated SARS-CoV-2 pathogenesis. https://doi.org/10.1101/2023.01.16.524211

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