University College London
Significant differences in how the nasal cells of young and older people respond to the SARS-CoV-2 virus could explain why children usually experience milder COVID-19 symptoms, according to a new study led by researchers from UCL and the Wellcome Sanger Institute.
Children infected with SARS-CoV-2 rarely progress to respiratory failure. However, the risk of mortality in infected individuals over 85 remains high. In this study, we investigated the cellular landscape and function of nasal epithelial cells grown ex vivo in children (under 12 years), adults (30 to 50 years), and older adults (over 70 years) in response to SARS-CoV-2 infection.
We showed that the cellular tropism of SARS-CoV-2 and the expression of ACE2 and TMPRSS2 in nasal epithelial cell subtypes differ among age groups. While ciliated cells are viral replication centers in all age groups, a distinct inflammatory goblet cell subtype emerges in infected pediatric cultures, showing high interferon-stimulated gene expression and incomplete viral replication.
In contrast, infected cultures from older adults show a proportional increase in basaloid cells, which facilitate viral spread and are associated with impaired epithelial repair pathways. We confirmed the age-specific induction of these cell types by integrating data from in vivo COVID-19 studies and validated that our in vitro model mimics the early epithelial responses to SARS-CoV-2 infection.
The study, published in Nature Microbiology, focused on the initial effects of SARS-CoV-2 infection on the cells first targeted by the virus: human nasal epithelial cells (NECs).
These cells were donated by healthy participants from Great Ormond Street Hospital (GOSH), University College London Hospital (UCLH), and the Royal Free Hospital, including children (0-11 years), adults (30-50 years), and, for the first time, elderly individuals (over 70 years).
The cells were then cultured using specialized techniques, allowing them to regrow into the different cell types found in the nose. Using single-cell RNA sequencing, which allows scientists to identify the unique genetic networks and functions of thousands of individual cells, the team identified 24 distinct epithelial cell types. The cultures from each age group were then either mock-infected or infected with SARS-CoV-2.
The researchers found that, after three days, children´s human nasal epithelial cells (NECs) responded rapidly to SARS-CoV-2 by increasing interferon (the body´s first line of antiviral defense), thereby restricting viral replication. However, this early antiviral effect became less pronounced with age.
The researchers also found that the NECs of elderly individuals not only produced more infectious viral particles but also experienced more cell damage and detachment.
The strong antiviral response in children´s NECs may explain why younger people tend to experience milder symptoms. On the other hand, the greater damage and increased viral replication found in the NECs of older individuals could be linked to the higher severity of the disease observed in older adults.
Project lead Dr. Claire Smith (Associate Professor at the UCL Great Ormond Street Institute of Child Health) said: "Our research reveals how the types of cells in our nose change with age and how this affects our ability to combat SARS-CoV-2 infection. This could be crucial in developing effective antiviral treatments tailored to different age groups, especially for older individuals who are at higher risk of severe COVID-19."
Co-lead author Dr. Kerstin Meyer (Wellcome Sanger Institute) said: “By conducting in vitro infections of epithelial cells with SARS-CoV-2 and studying the responses through single-cell sequencing, we gain a much more detailed understanding of the viral kinetics of infection and see significant differences in innate immune responses between cell types."
Children infected with SARS-CoV-2 rarely progress to respiratory failure, but the mortality risk in infected individuals over 85 remains high, despite vaccination and improved treatment options.
The research highlights the importance of considering age as a critical factor in both infectious disease research and treatment.
Co-lead author Dr. Marko Nikolic (UCL Division of Medicine) said: “It’s fascinating that when we remove immune cells from nasal samples, leaving only cultured nasal epithelial cells, we can still identify age-specific differences in our body´s response to SARS-CoV-2, which help explain why children are generally protected from severe COVID-19."
Dr. Smith added: “Understanding cellular differences at the start of infection is just the beginning. We now hope to investigate the long-term implications of these cellular changes and test therapeutic interventions using our unique cell culture model. This ‘gold-standard’ system is only possible thanks to the support of our funders and the willingness of participants to provide their samples.”
The team suggests that future research should consider how aging affects the body´s response to other viral infections.
In summary, we have shown that SARS-CoV-2 exhibits age-specific tropism in nasal epithelial cells, targeting goblet cells in children and secretory cells in older adults. Pediatric cells exhibit a strong antiviral response, leading to limited viral replication. In contrast, elderly cells suffer detachment and more epithelial damage. Impaired repair pathways and an increase in basaloid cells associated with fibrosis markers contribute to greater viral spread in older adults. These findings provide insights into the age-related pathogenesis of COVID-19 and demonstrate how impaired repair processes enhance SARS-CoV-2 infection in older individuals.
This study was funded by UK Research and Innovation (UKRI), the National Institute for Health and Care Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre, Wellcome, and the Chan Zuckerberg Initiative.
