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How do children overcome COVID-19? Innate immune system offers clues: Science Translational Medicine.

photo by pedro wroclaw via

A new article online, published September 21, 2020, on the preprint version of Science Translational Medicine, a subset of Science magazine, looks at the responses of children to SARS-COV-2 infection (COVID-19) and finds a difference in the serum concentrations of immune proteins.

Innate vs Acquired Immune Systems

First, a few words (oversimplified, a summary derived from Wikipedia) about the two main forms of immunity found in all vertebrates (higher animals, with spines): innate and acquired. The innate immune system is inherited from lower forms of life and includes basic responses to all pathogens (organisms which infect other organisms.) The acquired immune system evolved in higher animals and is primarily limited to vertebrates.

The innate immune system starts with a physical barrier (the skin and, inside, the endothelial cells lining the respiratory and digestive tracts.) It continues with specialized immune cells (often called white blood cells or leukocytes) that reside in every tissue of the body. Each individual cell also has innate immune components that include proteins called “toll-like receptors” or TLR. (See also a previous post in which I described a deficiency of TLR-7 which caused severe disease in twin brothers with COVID-19.) Each cell produces “cytokines” (cell-signaling proteins) when it is attacked.

The adaptive immune system is activated by the innate immune system and takes longer to respond. Its components include antibodies and higher forms of immune cells. Immune cells in the innate system (including “dendritic cells” present in all body tissues) break up pathogens and present parts of them (known as “antigens”) to cells in the adaptive immune system.

The acquired immune system develops a memory that enhances the body’s later response to a pathogen after it is defeated the first time. The memory includes antibodies, specialized proteins that are created for each individual type of pathogen in the days and weeks after an infection. Cells that produce antibodies are called “T lymphocytes.” The memory also persists in cells that give us “cell-mediated immunity” and are called “B lymphocytes.” Both types of lymphocytes can persist for decades after a single infection.

The acquired immune system kicks in when the innate immune system doesn’t immediately wipe out an invading pathogen. The acquired system takes four to seven days to rev up in humans.

New Findings About Children

From the abstract of the Science article:

We compared cytokine, humoral, and cellular immune responses in pediatric (children and youth, age < 24 years) (n=65) and adult (n=60) patients with COVID-19 at a metropolitan hospital system in New York City. The pediatric patients had a shorter length of stay, decreased requirement for mechanical ventilation and lower mortality compared to adults. The serum concentrations of IL-17A and IFN-γ, but not TNF-α or IL-6, were inversely related to age. Adults mounted a more robust T cell response to the viral spike protein compared to pediatric patients as evidenced by increased expression of CD25+ on CD4+ T cells and the frequency of IFN-γ+CD4+ T cells. Moreover, serum neutralizing antibody titers and antibody-dependent cellular phagocytosis were higher in adults compared to pediatric COVID-19 patients. The neutralizing antibody titer correlated positively with age and negatively with IL-17A and IFN-γ serum concentrations.

The higher concentrations of IL-17A and IFN-gamma in children are related to their innate immune systems, which respond to unfamiliar infections. IL-17A is a cell-signaling protein that promotes inflammation by starting a cascade of cell signals resulting in attraction of immune cells to areas of inflammation– areas invaded by pathogens like the novel coronavirus. IFN-gamma is another cell-signaling protein which is important to virus immune responses.

IL-6 (another cell-signaling protein) has a broad range of activity, both pro- and anti-inflammatory, and high levels are associated with severe COVID-19 with a poor prognosis. TNF-alpha (yet another cell-signaling protein, formerly known as cachectin and now called simply TNF) induces fever, cachexia (loss of weight associated with illness) and other signs of inflammation. At extremely high levels, TNF can cause septic shock. Both TNF and IL-6 inhibit viral replication (multiplication of viruses within a cell.)

Conclusions About Children

From the article:

 Dual cytokine (IL-17A and IFN-γ)-producing resident memory cells have been described in the lung (19) and a protective role for Th17 cells has been described in pulmonary infections (20).  Possibly, the higher concentrations of IFN-γ and IL17A in the serum of pediatric patients with COVID-19 reflected increased expression by cells in the respiratory tract, and these local cytokines may have protected the patients from progressive respiratory disease. …

The age-related difference in IL-17A concentrations in serum is consistent with described dysfunction of innate immune responses in older individuals (22). Decreased expression of pattern recognition receptors such as RIG-I by monocytes has been found with aging and has been postulated to account for reduced Type 1 interferon release. Invariant NKT cells, which secrete IL-17A and have cytolytic function, also decrease in number and function with aging (23). …

The bottom line is that higher levels of IL-17A and IFN-gamma appear to show the stronger innate immune response of children to SARS-COV-2 exposure and are probably related to robust reaction of cells (particularly dendritic cells) in the lung to infection. This stronger immediate immune response, not dependent on the acquired immune system but due to quick reaction by the innate immune system, may explain why children show fewer and milder signs of infection when COVID-19 occurs.

At the same time, delayed occurrence of the MIS-C syndrome probably is due to late over-reaction of the acquired immune system, two or more weeks after infection. This syndrome, while dramatic, usually has a more benign prognosis– that is, children usually recover from it (although not always.)

Lower levels of “serum neutralizing antibody titers and antibody-dependent cellular phagocytosis” in children appear to be due to the fact that the innate immune system has terminated the SARS-COV-2 infection quickly and stopped the acquired immune system from being fully activated.

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