by Gertrud U. Rey
It is still not entirely clear why children are less susceptible to severe COVID-19. Early hypotheses included the possibility that children may have a stronger innate immune response, which is the response that occurs upon an initial encounter with a pathogen. Results from a recent study support this hypothesis.
To clarify why children have an enhanced ability to control a SARS-CoV-2 infection, the authors of the study collected nasal samples from SARS-CoV-2-negative and SARS-CoV-2-positive children and adults ranging in age from 4 weeks to 77 years. The presence of viral RNA in samples from SARS-CoV-2-positive participants was confirmed by PCR. The samples were also analyzed for the presence of different cell types using single cell RNA sequencing, a method that reveals the RNA expression profiles of individual cells. The authors detected 33 different cell types in the upper respiratory tract of all tested individuals, including 21 immune and 12 epithelial cell subtypes. The differences in the cell compositions of children and adults were quite dramatic – while nasal samples from healthy adults rarely contained immune cells, samples from children contained high levels of almost every immune cell subset, with neutrophils representing a substantial portion of the cell population. Neutrophils are an essential part of the innate immune system because they accumulate quickly at a site of infection, where they ingest pathogens and recruit and activate other immune cells.
Despite this difference in cell composition in the nasal mucosa of children and adults, the expression level of ACE2 (the SARS-CoV-2 binding target), was similar in both age groups. This result is contrary to previous suggestions that children may express less ACE2, but it is consistent with reports indicating that the frequency of SARS-CoV-2 infection in children is similar to that of adults.
Sentinel cells of the innate immune system recognize invading pathogens by sensing structurally conserved molecular motifs in infectious microbes. This sensing occurs through various pattern recognition receptors on or in the immune cells present in most tissues, like the well-characterized RIG-I-like receptors. Together with two other proteins, MDA5 and LGP2, RIG-I-like receptors detect the presence of viral RNA inside our cells and trigger a cascade of events that mobilize immune cells such as macrophages, neutrophils, and dendritic cells to the site of infection. Once there, these immune cells produce pro-inflammatory signaling proteins known as cytokines, which then cue other responses and prime adaptive T and B cells for future functions. Sensing of viral RNA by RIG-I and MDA5 initiates the production of a cytokine called interferon, a signaling protein that triggers downstream protective defenses.
When the authors compared the baseline expression of RIG-I-, MDA5-, and LGP2-encoding genes in the upper respiratory tract epithelial cells of healthy children and adults, they found that healthy children expressed significantly higher levels of these genes compared to healthy adults and SARS-CoV-2-positive adults who were in the early phase of infection. Samples from healthy children also contained a subpopulation of cytotoxic T cells that was absent in adults, and these T cells produced high levels of interferon gamma, a cytokine that inhibits viral replication and induces macrophages to engulf and digest pathogens.
When children became infected with SARS-CoV-2, they produced significantly higher levels of interferon gamma compared to SARS-CoV-2-positive adults, both in the early and later phases of infection. This observation is particularly interesting when considering that impaired interferon responses are a hallmark of severe COVID-19 and that SARS-CoV-2 is highly susceptible to interferon treatment. Furthermore, samples from SARS-CoV-2-infected children contained a subpopulation of SARS-CoV-2-specific memory T cells that was nearly absent in adults, suggesting that children might have an increased ability to respond to future SARS-CoV-2 reinfections.
The increased numbers of innate immune cells and increased expression of pattern recognition receptor genes in the upper airways of children may facilitate a more efficient innate response to SARS-CoV-2 infection, leading to reduced viral replication and faster clearance of virus. This type of innate immune response seems to be delayed in older adults, and in an effort to “catch up,” may result in excessive inflammation, thereby ultimately causing more severe damage. Although there are likely more factors at play, this study brings us one step closer to understanding why COVID-19 is generally less severe in children.
All immune responses, from intrinsic to adaptive, need to be regulated – if left on indefinitely they will damage the host. The 
Hosts
The fact that viruses routinely and frequently cause disease shows that our defense mechanisms are imperfect. This occurs in large part because nearly every viral genome encodes one or more countermeasures to modulate host defenses. Influenza virus is no exception. One of the viral proteins, called NS1, is particularly adept at impairing the synthesis of interferons (IFN) by cells.