In a recent study published in the journal Nature Microbiologyresearchers investigated age-related differences in nasal epithelial cell (NEC) responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pediatric, adult, and older adult groups.
Study: Age-specific responses of the nasal epithelium to SARS-CoV-2 infection. Image credit: Designua / Shutterstock
Record
Despite effective vaccines, age remains the main risk factor for mortality from coronavirus disease 2019 (COVID-19). SARS-CoV-2 initially infects NEC, which is critical for understanding the progression to severe respiratory problems. Further research is needed to fully understand the mechanisms behind age-related differences in response to SARS-CoV-2, which could lead to targeted therapies and improved outcomes for different age groups.
About the study
Participants for the present study were recruited from five major hospitals in London, United Kingdom (UK), including Great Ormond Street Hospital National Health Service (NHS) Foundation Trust, Royal Free London NHS Foundation Trust, University College London Hospitals NHS Foundation Trust and the Whittington Health NHS Trust, between March 2020 and February 2021. All participants gave written informed consent and the study was ethically approved through the Living Airway Biobank, managed by the University College London (UCL) Great Ormond Street Institute of Child Health. People excluded from participation were smokers, people with active cancer or immunodeficiency, recent recipients of blood transfusions, and people with chronic respiratory conditions such as asthma or cystic fibrosis.
Nasal swabs were collected from healthy donors in three age groups—pediatric (0–11 years), adults (30–50 years), and elderly (≥70 years)—who had tested negative for SARS-CoV-2 and showed no respiratory symptoms in the seven weeks before sampling. Samples were collected using cytological brushes and immediately processed to preserve cell integrity, following strict guidelines.
NECs were cultured at an air-liquid interface, infected with SARS-CoV-2, and monitored for gene and protein expression changes, cell differentiation, and viral replication dynamics.
Schematic of method and model used to study SARS-CoV-2 infection of pediatric epithelial cells (P, <12 ετών), ενηλίκων (Α, 30-50 ετών) και μεγαλύτερων ενηλίκων (Ο, >70 years) of nasal epithelial cells.
Study results
In examining the cellular composition of NECs at different ages, a dataset of 139,598 cells was analyzed using single-cell ribonucleic acid (RNA) sequencing, revealing 24 distinct epithelial cell types or states. These ranged from basal cells, with subpopulations such as circular basal and basal epithelial-mesenchymal transition (EMT) cells, to secretory and ciliated cells, each categorized with unique gene expression patterns associated with various functions, including mucosal defense.
The study also noted age-related variations in the distribution of these cell types. Adults showed a greater abundance of basal/progenitor cells compared to children, a pattern consistent with findings from previous studies of nasal epithelium. Despite these differences, actin activity and expression levels of structural proteins such as tubulin showed no significant change with age. However, NEC cultures from older adults were observed to be thicker, suggesting a denser cellular arrangement without affecting the integrity of the epithelial barrier.
A striking finding in pediatric cultures was the increased presence of a specific goblet cell type, indicating a change in cellular state not seen in adults or elderly subjects. Despite similar levels of total protein entry factors of SARS-CoV-2 in all age groups, messenger RNA (mRNA) levels of these proteins were clearly higher in pediatric cups, suggesting different susceptibility to viral infections between ages.
When investigating viral replication dynamics, NEC cultures infected with an early-lineage SARS-CoV-2 strain showed no significant differences in the number of viral reads over time between age groups. However, the type of infected cells differed, with younger subjects showing infections concentrated in fewer cell types than adults and older adults. Interestingly, the elderly showed greater spread of viral infection within the culture, evidenced by a higher percentage of cells expressing viral RNA.
The study expanded on the effects of SARS-CoV-2 on cellular phenotypes, revealing that infection led to reduced culture thickness and compromised epithelial integrity in adults and older adults. A significant increase in basal cell mobilization was also observed in older adults, suggesting an increased response to infection involving cellular repair mechanisms and possibly contributing to more severe disease outcomes. Additionally, NECs of older adults showed a greater tendency to express markers associated with tissue injury and fibrosis, which may explain the more pronounced physical and clinical effects of COVID-19 seen in older populations.
conclusions
In summary, the study analyzed 139,598 NECs at different ages, revealing 24 different cell types using single-cell RNA sequencing. It showed age-related differences in cellular distribution, with adults having more basal/progenitor cells and the elderly showing thicker NEC cultures. Pediatric cultures had increased specific goblet cells, indicating variable susceptibility to SARS-CoV-2. While virus replication was consistent across all ages, the elderly showed a wider spread of infection. Infection altered cellular phenotypes, reducing epithelial integrity in adults and increasing markers of tissue damage in older adults, highlighting the importance of considering age in COVID-19 strategies.
