Throughout the ongoing pandemic, it was observed that children were less affected and those affected had milder symptoms compared to the adults. This, better defence of children against the SARS-CoV-2 infection is attributed to their innate immunity. Early and immediate response is triggered due to the cell-intrinsic innate immunity which is mostly mediated through pattern recognition receptors (PRR) and the type I and III interferon (IFN) system.

To understand the higher capacity of children for controlling SARS-CoV-2 infection at an early stage a study was done comprising of SARS-CoV-2 negative and SARS-CoV-2 positive children (n=42) and adults (n=44), comprising 268,745 cells in total. Samples from the upper airways (nose) were collected from individuals aged 4 weeks to 77 years with a positive SARS-CoV-2 PCR result. Based on the single-cell RNA sequencing data we identified 33 different cell types or states in the upper respiratory tract of these individuals including 21 immune and 12 epithelial cell subtypes. 

A significant difference was observed in the composition of the immune cell and epithelial cell compartment in the nasal mucosa between the pediatric and adults. From the studies, it was observed that there was an increase in the amount of each immune cell subset, with neutrophils being the most dominant. Children’s neutrophils showed an activated phenotype after getting infected, which was more pronounced than in infected adults.

Control of SARS-CoV-2 infection needs an optimal early and coordinated innate immunity, which is activated by various pattern recognition receptors (PRRs). Recent studies showed that MDA5 (IFIH1) was one of the major PRR for SARS-CoV-2 in epithelial cells with a small role being played by RIG-I (DDX58).

The study showed, that there was a significantly higher basal expression level of the genes coding for RIG-I, MDA5 and LGP2 in epithelial cells in the upper respiratory tract of healthy children when compared to adults.  Prompt and immediate sensing of SARS-CoV-2 by MDA5/LGP2 in infected epithelial cells was triggered due to the higher basal expression of these PRRs. It was observed that in children, there was an increased expression of these PRR genes in the airway epithelial cells compared to SARS-CoV-2-positive adults, particular in the early stages.

After, sensing a viral infection,  a signal is released through the IRF3/NFκB, which leads to the expression of primary antiviral effectors and also antiviral cytokines such as IFNβ and IFNλ. The IFNs start acting on the epithelial cells in an autocrine and paracrine manner and increases MDA5/LGP2 responsiveness in the tissue and induces a broad range of IFN-stimulated genes (ISGs). It was observed that both in the early and late infection phases,  the magnitude of ISG expression in children surpassed that of the infected adults.

Also, the study concluded that innate immune cell activation was enhanced in children. Non-resident macrophages (nrMa) monocyte-derived macrophages (moMa) and CD11c+ dendritic cells (CD11c_mDC) were most interactive among immune cells and showed higher activation status in children. Further, the enhanced expression level of IFIH1 in moMa, nrMa and CD11c_mDC and a significant increase of TLR2 in moMa and nrMa were observed in children infected with SARS-CoV-2, suggesting that these cells may also be important in sensing the virus at the earliest and production of IFN. 

Among the identified subpopulation, KLRC1 (NKG2A)+ cytotoxic T cells (CTL2) were most prominently present in children. NKG2A was also important in controlling over activation, preventing apoptosis and sustaining the virus-specific CD8+ T cell response. In SARS-CoV-2 negative children to IFNG was high. Also, potent chemoattractant CCL5 was increased in children with the infection. The predominance and the cytotoxic potential of the cytotoxic T cell subset was essential for killing virus-infected cells and this provided more evidence that children and better anti-virus response.

Thus from the data available from the study,  it is clear that the epithelial and immune cells of the upper airways (nose) of children are pre-activated and primed for virus-sensing, which helps in the early detection of the infection and reduces the chances of complexities.

References

1. Loske J, Röhmel J, Lukassen S, Stricker S, Magalhães VG, Liebig J, et al. Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children. Nature Biotechnology. 2021.