Researchers are studying differences in reactions to SARS-CoV-2 infection between children and adults

The 2019 coronavirus outbreak (COVID-19) has claimed more than 2.67 million lives in less than a year and a half. However, it is uncommon in children, with less than 2% of cases in individuals under the age of 19. Most of these are relatively mild, with clinical features of COVID-19 malignancy. very rare in this age group.

A new and timely study, published on the medRxiv* preprint server, examining the differences in the response to acute respiratory disease coronavirus syndrome 2 (SARS-CoV-2) in adults vs children to help understand how the disease develops and develops coming forward.

The virus binds to the host cell surface protein, an enzyme that converts angiotensin (ACE) 2, to achieve cell entry. Several studies, but not all, reveal age- and stress-dependent ACE2 sensitivity, which leads to disease severity in children.

The current study aims to define a protective landscape in the blood and high airway from early life to adulthood. During this period, immune development occurs from the immune tolerant state in fetal life to a later pro-inflammatory state, as the individual is exposed to antigens and pathogens.

The researchers used multi-omics data from single-cell data sets in 30 healthy children, derived from nasal and tracheal brushes and peripheral blood mononuclear cells (PBMCs), to explain normal developmental changes in several cell types. The cells came from the airway (42) and blood (31), and the population covered ages from childhood to adolescence.

They also described cells from pediatric and adult COVID-19 patients and compared these results with the reference data.

Airway epithelial cells in healthy children

The researchers found 15 different cell types, mostly in two groups. One of them was the pathway of differentiation from basal cells to secretory, including basal, secretory, goblet 1 and 2, and squamous cells. The second was the connected browser.

Epithelial cell types remained stable in association with age. However, goblet 2 and secretory cells were significantly more common in the nasal epithelium compared to the trachea or bronchi.

Novel cell type

The scientists also discovered a new type of epithelial cell transition between secretory and ciliated phenotypes, in children with and without COVID-19. This is among the cell types that show a marked antiviral profile, along with neutrophil recruitment. These were called inflammatory epithelial stem cells (IETCs), because they were high in inflammatory signals, but also expressed linked cell signals and secretory genes.

These cells were found mainly in COVID-19 patients but also in healthy children, which may appear to occur both at the time of development and also at the time of recovery.

The IETCs may be a unique pathway for differentiation in the replacement of dying connected cells. This accounts for the decrease in primary gas cell numbers, i.e., basal I cells. These were observed to regain their numbers in convalescent patients.

Signature of neutrophil recruitment has been observed in IETCs, including traces of serum amyloid protein and calprotectin, both of which are expressed in injury and inflammation. The latter is related to COVID-19 mild anti-inflammatory.

Calprotectin is mainly found in myeloid cells, but in the present study, it was found to be expressed in epithelial cells from the nose of an adult COVID-19 patient. This confirms how epithelial cells are crucial in initiating a tissue-immune response.

Airway cells in COVID-19

In COVID-19 patients, IETCs, goblet 2 and ciliated cells were the richest and showed the highest viral readings.

This corresponds to the highest levels of ACE2 and TMPRSS2 expression in these cells in healthy individuals. The researchers post that these cells are enlarged due to a higher rate of reduction to replace those that died as a result of infection. This phenomenon was observed in the lower airways after infection.

Basal cells were reduced. In adults, but not in children or convalescents, acute COVID-19 was associated with higher ACE2 expression.

Other viral entry receptors include NRP1, BSG and TFRC, but these did not show an association with active infectious cells from humans with high viral readings.

Other cells with viral readings contained lymphocytes and macrophages, but it is unclear whether this indicates true disease or phagocytosis. No viral readings were observed in PBMCs in the COVID-19 patients.

Immune blood cells in healthy children

Across age groups, the researchers found that the image of naïve lymphocytes showed an improvement in their gene expression profile. Several expressed genes identified increased proliferative potential, and specific immune functions, possibly with increased cytotoxicity.

Both naïve T and B cells have thus entered the bloodstream before the first year of life, and continue to develop to their mature state.

Dendritic cells, Tregs and naïve B increased in size from newborns to infants, but decreased thereafter. Modified immune cells such as CD8 + cytotoxic T lymphocytes (CTL), plasma cells and gamma delta (g / d) T cells were all high in precursors, possibly due to their exposure to higher antigen exposure.

B cells were immobilized and immobilized, as well as diffuse cells, usually in the youngest age group, but toward the other end, in adolescence, mucosal-linked invariant T cells (MAIT) became involved. increase.

Naïve cells began to decline with age and were very low in those over 65 years, indicating a sustained stimulus over a lifetime of exposure.

Lymphocyte clones expand in adults

In adults, T and B cell clones, including various T cell subtypes, have been expanded, but not in children, and especially in COVID-19 patients. This clonal enlargement indicates the immune immune response of a memory cell.

COVID-19 immune blood cells

The biggest change in blood in children with COVID-19 was an increase in B and T naïve cells, regulatory T cells (Tregs) and lymphoid tissue cells (ILCs). This occurred despite an average lymphocyte count. This confirms earlier reports that lymphopenia is less common in pediatric COVID-19.

This may be due to the release of large numbers of naïve and neural cells from the thymus and bone marrow or the migration of mature cells to the site of infection. These trends were reversed in rehabilitative children.

At the same time, natural killer cells (NK) and monocytes were lost in children, again, perhaps, due to migration to the site of the disease.

Airway cells in COVID-19 and with age

The scientists again saw several changes in healthy children with age. This included a rapid decrease in neutrophils, activated macrophages and monocytes, from neonatal onwards. CD8 T effect cells, γ / δ cells and MAIT cells were high through infancy.

Adolescents did not show the same level of variation in airway cells with age.

With COVID-19, children with extensive immunosuppression had a significant increase in B cell subtypes, follicular dendritic cells and naïve T cells, all of which are associated with a strong immune response.

Lack of correlation between airway and blood immune cells

The researchers also found that there was a strong association between most blood types in blood and the airway. However, higher lymphocyte density was not closely associated with monocytes and NK cells.

In adults with acute COVID-19, lymphocyte frequency and the relationship between T cells in the blood and airways varied significantly.

Lymphocytes also showed greater proliferation of memory cells and effect in adults but not children with COVID-19.

What is the impact?

The response to SARS-CoV-2 in adults versus children strongly reflects the fundamental changes in the protective view we see over a lifetime. ”

The most significant difference between adults and children with SARS-CoV-2 infection was the highest naïve immune status in the first year of life, but altered memory cell memory responses in adults.

In adults, lymphopenia with increased CD8 T effect cells is normal in COVID-19, while CD4 and CD8 cells are increasingly exacerbated in more severe disease. Plasma cells and plasmablasts are high in malignancy, usually the IgG-producing subtype.

These differences are due to the different structures of the immune repertoire in children and adults.

The study also showed changes in the correlation of airway immune cells and those in the blood with active COVID-19. Thus, the two immune cell subsets deserve separate study.

Clonal lymphocyte proliferation in adults results in lower immune diversity than in children. This has been reported to be a symptom of COVID-19 malignancy in adults, partly explaining the less severe manifestation in children.

Children and adults with true COVID-19 did not show a strong interferon (IFN) response in airway cells, compared with the age-dependent increase in healthy children. This is also in contrast to the high IFN response in COVID-19 adult patients with moderate or mild infection. The strongest IFN response was in secretory and goblet cells.

Further studies will be needed to determine whether this lack of IFN response is common to all children with COVID-19 or just true cases. If the latter, it may explain why ACE2 is not regulated in children with COVID-19.

Despite the neutrophil recruitment signals, more research is also needed to understand how neutrophils change with age and with COVID-19 in children and adults. These findings may provide insight into how children develop the epithelial and immune response in health and in COVID-19.

* Important message

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be seen as final, guiding health-related clinical practice / behavior, or treated as fixed information.