Innately Immune

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.

4 thoughts on “Innately Immune”

  1. How does the fact that children’s immune system is already supercharged by all the vaccinations they are receiving, and the studies that DTap and MMR antibodies cross-react with Covid virions affect this study?

  2. Hello.

    Would you comment on the probability that a strong (youthful?) innate response may clear a virus before a humoral response is triggered?

    “Severe” and “Long” Covid are both associated with an observed presence of circulating autoantibodies in recovering patients.
    It is thought that protein homology between viral and human proteins may result in production of new antibodies that are equally capable of binding with virus or human antigens.

    Presumably, if a strong innate response clears the virus before a humoral response is triggered, the risk of autoantibody induction would accompany the probability of new antibody production: minimized or eliminated?



  3. Just want to comment to say thank you for these thoughtful post(s). Your insightfulness and ability to communicate relatively esoteric topics in to a general audience. The audience has to be perhaps relatively educated and willing to look a few things up along the way, but I feel like I have a very sober understanding of this virus in part because of your posts here. Cheers.

  4. (Sad to see that even this excellent science site is being targeted by spammers like ‘Jasmine’ above.)

    On topic: it’s good to read that such detailed, well constructed, research is possible in children, without the need for scary blood draws, that must be a powerful deterrant.

    It would seem logical that the increased numbers of immune cells in children’s upper respiratory mucosae, is due to there being a much greater number of unfamilliar compounds and organisms encountered every day, than there will be with increasing age. It seems likely that a child’s immune system is always in a state of activity, identifying and ‘cataloguing’ every new thing that is encountered, whereas, the older one gets, the fewer unfamiliar things are encountered, and a smaller ‘standing army of policemen, and, librarians’ is kept at the ready to deal with the occasional newcomer, which makes for a slower initial response when something dangerous turns up.

    Might this imply that those with overactive immune systems and allergies could share some of the advantages of youth in being inately ready to combat SARS-CoV-2?

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