The local and systemic response to SARS-CoV-2 infection in children and adults

Abstract

While a substantial proportion of adults infected with SARS-CoV-2 progress to develop severe disease, children rarely manifest respiratory complications. Therefore, understanding differences in the local and systemic response to SARS-CoV-2 infection between children and adults may provide important clues about the pathogenesis of SARS-CoV-2 infection. To address this, we first generated a healthy reference multi-omics single cell data set from children (n=30) in whom we have profiled triple matched samples: nasal and tracheal brushings and PBMCs, where we track the developmental changes for 42 airway and 31 blood cell populations from infancy, through childhood to adolescence. This has revealed the presence of naive B and T lymphocytes in neonates and infants with a unique gene expression signature bearing hallmarks of innate immunity. We then contrast the healthy reference with equivalent data from severe paediatric and adult COVID-19 patients (total n=27), from the same three types of samples: upper and lower airways and blood. We found striking differences: children with COVID-19 as opposed to adults had a higher proportion of innate lymphoid and non-clonally expanded naive T cells in peripheral blood, and a limited interferon-response signature. In the airway epithelium, we found the highest viral load in goblet and ciliated cells and describe a novel inflammatory epithelial cell population. These cells represent a transitional regenerative state between secretory and ciliated cells; they were found in healthy children and were enriched in pediatric and adult COVID-19 patients. Epithelial cells display an antiviral and neutrophil-recruiting gene signature that is weaker in severe paediatric versus adult COVID-19. Our matched blood and airway samples allowed us to study the spatial dynamics of infection. Lastly, we provide a user-friendly interface for this data as a highly granular reference for the study of immune responses in airways and blood in children.

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19

“…Finally, we directly mapped the developmental transitions among nasal epithelial cells within control (Figure 2P) or COVID-19 participants only (Figure 2Q). Cells from control participants poorly populated the intermediate regions that bridge secretory and goblet cell types to mature ciliated cells (Yoshida et al, 2021). Conversely, regions annotated as multiple secretory cell subsets and developing ciliated cells are uniquely captured from COVID-19 participants.…”

Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant

“…A delayed response, compared to rapid viral RNA replication, suggests effective innate immune antagonism and evasion by SARS-CoV-2 early in infection 13,24 . Furthermore, the gene expression changes observed during late innate responses in infected Calu-3 cells reflect the overarching inflammatory signatures observed at the site of infection and those associated with severe COVID-19 [25][26][27][28] . Here, we used the Calu-3 cell model to evaluate differences between B.1.1.7 and wave one SARS-CoV-2 viruses.…”

Respiratory epithelial cell responses to SARS-CoV-2 in COVID-19

“…7 Furthermore, single cell analyses of airway epithelial cells from adult and paediatric patients identified reduced interferon responses in epithelial cells and a higher proportion of innate lymphoid and naïve T cells in peripheral blood in COVID-19 paediatric patients compared with adults. 70…”