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

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 c...

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Published in:bioRxiv 2023-01
Main Authors: Woodall, Maximillian, Ana-Maria Cujba, Worlock, Kaylee B, Case, Katie-Marie, Masonou, Tereza, Yoshida, Masahiro, Polanski, Krzysztof, Huang, Ni, Lindeboom, Rik Gh, Lira Mamanova, Bolt, Liam, Richardson, Laura, Ellis, Samuel, Palor, Machaela, Burgoyne, Thomas, Pinto, Andreia, Moulding, Dale A, Mchugh, Timothy D, Saleh, Aarash, Kilich, Eliz, Mehta, Puja, O'callaghan, Chris, Zhou, Jie, Barclay, Wendy, De Coppi, Paolo, Butler, Colin R, Vinette, Heloise, Sundando Roy, Breuer, Judith, Chambers, Rachel C, Heywood, Wendy E, Mills, Kevin, Hynds, Robert E, Teichmann, Sarah A, Meyer, Kerstin B, Nikolic, Marko Z, Smith, Claire M
Format: Article
Language:English
Subjects:
ACE2
Age
Angiotensin-converting enzyme 2
Epithelial cells
Genomes
Inflammation
Pediatrics
Progenitor cells
Severe acute respiratory syndrome coronavirus 2
Stem cells
Tropism
Vaccination
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Summary: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 (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. A video explaining this work can be found here - https://youtu.be/uExP4bx6D_A .Competing Interest StatementIn the past three years, SAT has received remuneration for consulting and Scientific Advisory Board Membership from GlaxoSmithKline, Foresite Labs and Qiagen. SAT is a co-founder, board member and holds equity in Transition Bio. All other authors declare no conflicts of interest.Footnotes* Main Figure file order has been updated. Previous version had Figure duplication
DOI:10.1101/2023.01.16.524211