Exploring why children have milder COVID-19 infections compared to adults

By Dr. Sanchari Sinha Dutta, Ph.D.Dec 23 2021Reviewed by Aimee Molineux

A study recently published in the journal Nature has revealed that an activated pre-exposure innate interferon response in airways together with significantly reduced systemic interferon-stimulated populations are associated with relatively milder severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children.

Background

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, it has been observed that SARS-CoV-2 causes relatively milder infections in children than adults. Similarly, the prevalence of severe COVID-19 as well as the disease-related death rate are significantly low among children.

Being a respiratory virus, SARS-CoV-2 primarily attacks airway epithelial cells. The angiotensin converting enzyme 2 (ACE2) receptor expressed in airway epithelial cells acts as an entry point for the virus. The expression of ACE2 is significantly higher in adults compared to than in children. This might be a reason of lower disease severity in children. However, the exact difference in airways and the systemic immune responses to SARS-CoV-2 between children and adults is still uncertain.   

In the current study, the scientists have characterized the dynamics of SARS-CoV-2-induced immune responses in children and adults. They have collected respiratory (nasal, tracheal, and bronchial) and blood samples from adult and pediatric COVID-19 patients and healthy controls. They analyzed the samples with single-cell transcriptomics combined with protein profiling.   

Study design      

Overall, 19 children and 18 adults with asymptomatic to severe COVID-19 were enrolled for the study. In addition, 41 healthy children and adults were enrolled as controls. A dataset of 659,217 cells was generated for single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing (CITE seq).

Novel airway cell types

The plasticity of the airway compartment is known to be associated with several basal, goblet, ciliated, and transit epithelial type 1 and type 2 cells. In this study, transit epithelial type 1 cells were observed in both COVID-19 patients and healthy children. This indicates that these cells are required for development and tissue regeneration.

In SARS-CoV-2-infected neonates, a distinct cluster of monocytes secreting interleukin 6 (IL-6), G protein-coupled bile acid receptor 1 (GPBAR1), and CXCL10 was identified.

Regarding SARS-CoV-2 infection in airway epithelium, the highest viral load was detected in goblet type 2 inflammatory cells, followed by basal and transit epithelial cells and ciliated cells. In contrast to ACE2 expression in adults which is induced by interferon and SARS-CoV-2 infection, no significant induction in ACE2 expression was observed in children with COVID-19.

In adults with COVID-19, the most highly enriched cell types were transit epithelial type 1 and goblet type 2 inflammatory cells. As hypothesized by the scientists, the number of transit epithelial cells might have increased to replace dying ciliated cells.

In children with COVID-19, no significant changes in epithelial cell types were observed. However, a significant increase in IL-6 secreting monocytes was observed. In healthy children, increased levels of monocytes, reduced levels of CD8+ T cells, and expansion of the B cell population was observed. These findings indicate a shift from innate to adaptive immunity.

Distinct characteristics in children and adults

In adult COVID-19 patients, a significant induction in interferon response was observed in nasal epithelial cells, which reduced to a normal level after recovery. In contrast, nasal epithelial cells isolated from children showed an already activated interferon signaling, which increased slightly after SARS-CoV-2 infection. A similar pattern was observed for TNF signaling and neutrophil migration. In nasal immune cells, the induction in interferon response was higher in children than adults.  

Regarding systemic interferon responses, a significant induction was observed in both epithelial and immune cells of asymptomatic or mildly symptomatic adult COVID-19 patients. In children, this response was more robust in immune cells than in epithelial cells.

Regarding blood immune signature, significantly increased levels of CD8+ cytotoxic T cells and CD45RA-reexpressing effector memory cells were observed in adult COVID-19 patients. An induction in interferon-stimulated subpopulations (natural killer cells, B and T cells, and hematopoietic progenitor cells) was also observed in adult patients. In contrast, an induction in naïve lymphocytes and a reduction in natural killer cells and CD4+ cytotoxic T cells were observed in children with COVID-19. These observations indicate that in children, the immune response to SARS-CoV-2 is mostly restricted to airways; while in adults, systemic infection and inflammation are much higher than in children.

Crosstalk between local and systemic immune responses

A strong correlation between cell-type proportions in blood and nasal samples was detected in the study. Specifically, SARS-CoV-2-infected nasal epithelial cells and nasal dendritic cells strongly correlated with systemic interferon stimulation.

Further analysis revealed that nasal plasmacytoid and conventional dendritic cells trigger the production of type I and type III interferons at a very early stage of infection.  

Study significance

Overall, the study findings demonstrate that a slight induction in airway interferon response and a massive reduction in systemic interferon-stimulated populations upon SARS-CoV-2 exposure is primarily responsible for a relatively milder COVID-19 in children.