Unraveling the mystery of why children are better protected from Covid than adults

The immune system uses a special mechanism to protect children from novel viruses—and it typically saves them from a severe course of Covid-19 in two different ways. In the mucous membranes of their airways, it is much more active than that of adults. In children, this system reacts much faster to viruses that it has never encountered, such as pandemic pathogens. At least, that is what a recent study by Irina Lehmann of the Berlin Institute of Health at Charité and her colleagues suggests.

The researchers examined differences in the cell types of the mucous membranes of children and adolescents. As the team reports in Nature Biotechnology, children do not only have many more immune cells in their mucous membranes; they also more quickly produce type I interferons, which are crucial for fighting viruses. As a result, these key molecules may also provide protection from the dysregulation of the immune system that occurs in many severe cases of Covid-19.

Faster Virus Fighters

“The defense against viruses works on two levels. First, you get the antiviral response within the cells through receptors that, for example, induce the production of interferon,” Lehmann explains. “The second level [is] the immune cells in the tissue, such as activated killer cells and neutrophils.” The study carried out by her group shows that these two levels of viral control are on high alert in children. The team analysed almost 270,000 cells from swab samples taken from the nasal mucosae of people aged between four weeks and 77 years. About half of them were infected with SARS-CoV-2, the virus that causes Covid.

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The samples also show that the children’s cells produce larger quantities of immune receptors that recognise viruses and trigger the immune response. One such receeptor molecule, MDA5, is a sensor for foreign RNA found in many viruses, including SARS-CoV-2. It also directs the production of type I interferons, which are crucial to the innate, or rapid-response, immune system’s ability to fight viruses. They activate immune cells and put them in a special state of vigilance that makes it difficult for viruses to multiply.

“The interferons are extremely effective against virus infections,” explains Marco Binder of the German Cancer Research Center in Heidelberg, a co-author of the Nature Biotechnology study. As an effective countermeasure, however, the novel coronavirus has its own proteins that prevent interferons from being produced. “SARS-CoV-2 multiplies very quickly in cells, and this means that the virus proteins are also formed very quickly,” says Binder, who researches interferons. “And they suppress the interferon system so dramatically that we see only minimal or no interferon production in cell cultures when there is an infection.”

Interferon’s Dual Roles

In cell cultures of lung epithelial cells, Binder tested whether the larger numbers of MDA5s, as observed in children, might preserve the interferon reaction. Adults have very few of these receptors—the molecules have to be produced from scratch in the event of an infection. This costs time, which SARS-CoV-2 uses to stifle the entire immune signaling system. Children seem to be protected from this happening because of the stronger basic activation of MDA5 and similar receptors. In fact, Binder’s experiments showed that, in children, SARS-CoV-2 is simply too slow to prevent the cells from producing interferons.

Thus, children have virtually double protection against a severe course of SARS-CoV-2. Type I interferons do more than just warn the body about viruses. The signaling molecules regulate a number of processes in the general immune response. If they are absent during a SARS-CoV-2 infection, studies suggest, the body's defenses get out of step at the worst possible moment. The spread of the virus causes tissue damage, which in turn stimulates the immune system to fight the pathogen more violently.

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Because of the lack of type I interferons, however, the defense reaction is already in a dangerous imbalance and overshoots the target. As a result, the immune reaction causes massive tissue damage in the lungs even with a severe course of SARS-CoV-2. Other study results also indicate the crucial role of interferons in this process, which causes people with congenital defects in the type I interferon response—or autoantibodies against these signaling molecules—to confront a high risk of getting very seriously ill with Covid-19.

Children Still Get Seriously Ill

Children benefit from the fact that their supersharp immune system makes interferon react faster than SARS-CoV-2 prevents its production. “Conversely, if the concentration of MDA5 is increased, you skip the first step in which the protein first has to be upregulated,” Binder explains. “And that’s why the cell immediately produces measurable amounts of interferon when it comes into contact with the virus—before SARS-CoV-2 even has a chance to intervene.”

If a child’s interferon system is disturbed, however—because of a hereditary defect, for example—this protective effect disappears. That could possibly explain why even a few apparently healthy children and young people still get sick, Binder says. But the important point is that, in general, children can fight an unknown virus very quickly and effectively.

The effect also continues at the second level of the immune reaction because the necessary immune cells, such as activated killer cells, are already there and ready. One of the key findings of Lehmann and her colleagues’ study is that children have many more of these cells in their mucous membranes than adults. “The fact that the immune cells are already in the tissue gives you a head start, because all these cells do not have to be called up by signaling substances,” Lehmann says. “Of course, it makes a difference if you have one day less unhindered reproduction of the virus in the tissue.”

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Why Adults Remain Unprotected

The results of the study indicate that the immune system of children is designed to fight viruses particularly effectively when it first encounters them. Experts such as influenza researcher Peter Palese of the Icahn School of Medicine at Mount Sinai in New York City, who was not involved with the work, therefore suspect that children are generally better off than adults in pandemics—an effect that was presumably observed as early as 1918. Adults have to rely on the adaptive immune response—the specific protection provided by antibodies and T cells for individual pathogens that only develops a while after contact with the virus.

This proves to be a significant disadvantage in a pandemic. In contrast to seasonal respiratory pathogens, which one was usually able to intercept as a child, thanks to the effects of a sharpened immune system, adults are particularly defenseless against a new virus. This is apparent with Covid-19, as witnessed by the rate of serious illnesses and deaths, which increase almost exponentially within the aged population.

But why do only children have this highly effective protection? There are several reasons, Binder explains. “If the body had always activated this [process], it would of course create an incredible selection pressure on the pathogens,” he says. The viruses would have adapted long ago. In addition, the body cannot afford this system in the long term. “Of all signaling systems, the interferon response causes the greatest change in the cell’s genetic activity,” Binder says. If this response was left on permanently, it would have massive effects on cell activity and thus the body as a whole.

This is by no means just a theoretical problem. “It is known that people with congenital overactivation of this interferon system usually suffer from very serious inflammatory diseases,” Binder says. So the price of the interferon antiviral superweapon is that it has to be carefully kept under lock and key. As a result, SARS-CoV-2 can defuse it—and not only break through this line of protection but also throw the entire body’s defense system out of step. In our first years of life, however, we actually seem to be one step ahead of viruses.