COVID-19: Why immature immune system of Children is leading the way?

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COVID-19: Why the immature immune system of Children is leading the way?

After the extremely low incidence of COVID in New York City in the early summer of this year, the number of children who tested positive for SARS-CoV-2 began to rise.

Innate immunity may explain why children have better resistance to this virus, but the COVID-19 Delta variant brings new unknowns.

At the beginning of last year, the Children’s Hospital in New York City had to take measures to deal with the catastrophic COVID-19 outbreak. Betsy Herold, a pediatric infectious disease doctor and head of the virology laboratory at the Albert Einstein College of Medicine, said they all had to learn quickly (or half-learned) how to take care of adults.

The reason is: when the entire city’s hospitals are crowded with patients, the pediatric wards are relatively quiet. Children are protected to some extent, and are not affected by the most serious diseases.

Data collected by the US Centers for Disease Control and Prevention (US Centers for Disease Control and Prevention) from hospitals across the country show that people under the age of 18 accounted for less than 2% of patients hospitalized due to COVID-19 (3 From January to the end of August 2021, a total of 3649 children were admitted to the hospital).

Some children are indeed very sick, and more than 420 children have died in the United States. But most of the people who are seriously ill are adults, and this trend has been confirmed in many parts of the world.

This makes SARS-CoV-2 somewhat abnormal. For most other viruses, such as influenza and respiratory syncytial virus, young children and the elderly are usually the most vulnerable; the risk of adverse consequences by age can be represented by a U-shaped curve. But for COVID-19, the younger end of the curve is largely cut off. Kawsar Talaat, an infectious disease doctor at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, thinks this is remarkable. One of the few fortunate things about this pandemic is that children are relatively spared.

However, to immunologists, this phenomenon is not entirely surprising. For other viruses, adults have an experience advantage. Through previous infections or vaccinations, their immune systems have been trained to deal with similar pathogens. The novelty of SARS-CoV-2 leveled the playing field and showed that children are better at controlling viral infections.

Dusan Bogunovic, an immunologist and geneticist at the Icahn School of Medicine in Mount Sinai, New York City, said they always think of children as bacteria factories. But this is not because children’s immune systems are not working, they just lack experience.

Research has begun to reveal that the reason why children perform well against COVID-19 may be due to the innate immune response-the body’s rough but rapid response to pathogens. Herold believes that children seem to have an innate response, that is, “has been activated and ready to use.” But she added that more research is needed to fully support this hypothesis.

The emergence of Delta variants makes the search for answers even more urgent. The report shows that in the United States and elsewhere, children are beginning to account for a larger proportion of reported infections and hospitalizations. These trends may be due to the high transmission rate of Delta variants and the fact that many adults are now protected by vaccines.

Currently, there is no clear evidence that children are more susceptible or more affected by Delta variants than early variants. However, SARS-CoV-2, like all viruses, is constantly mutating and getting better and better at evading the host’s defenses.

This may make it possible to understand the protective role of children in response to SARS-CoV-2. More important. Lael Yonker, a pediatric pulmonologist at Massachusetts General Hospital in Boston, said they did not notice age-related differences in immune response because these differences had not previously had significant clinical significance. But COVID-19 emphasizes that they need to better understand these differences.

Brainstorming

Why are children better at controlling SARS-CoV-2 than adults? At first, the researchers believed that children were just not infected that frequently. The data shows that this is indeed the case, at least the situation is similar (children under 10 may be slightly less susceptible to infection).

The American Academy of Pediatrics found that until the end of last month, about 15% of all COVID-19 cases in the United States were people under the age of 21—that is, more than 4.8 million young people. In India, a survey of SARS-CoV-2 antibodies produced after infection or vaccination found that more than half of children aged 6-17 and two-thirds of the population have detectable antibodies.

Obviously, children are being infected. Therefore, perhaps the virus cannot replicate in them as it does in adults. Some researchers have suggested that children may have fewer ACE2 receptors (viruses use these receptors to enter and infect cells).

There is conflicting evidence that there are age-related differences in the expression of ACE2 in the nasal cavity and lungs, but when scientists measure the “viral load” (viral load, the concentration of viral particles) in people’s upper respiratory tract, they have not found There is a clear difference between children and adults.

In an analysis of 110 children published as a preprint on June 3, researchers found that infants to adolescents may have a high viral load, especially shortly after being infected. Yonker, who led the study, said that not only is the virus there and can be detected, but it is also a live virus, which means that these people are also infectious.

Another proposal is that children with runny noses throughout the year may be more likely to be exposed to other coronaviruses that cause the common cold. Therefore, a group of antibodies are ready at any time and have the ability to bind to the pandemic coronavirus. But a lot of evidence shows that adults also have this immunity. The shocking thing is that these “cross-reactive” antibodies do not provide any special protection, and if any, they may cause false reactions.

After basically negating these hypotheses, Herold et al. began to study whether there are any special features in the immune response of children that benefit them.

Some clues circulate in the blood of those infected. In a study comparing 65 people under the age of 24 with 60 elderly people, Herold et al. found that, overall, younger patients (with milder symptoms) produced similar levels of antibodies to older people. However, the level of special antibodies and cells related to adaptive immune response in young people has decreased.

The adaptive immune response is a weapon in the immune system that recognizes pathogens and helps them quickly eliminate them when they reappear. Specifically, children have low levels of “neutralizing” antibodies that prevent SARS-CoV-2 from infecting cells; antibodies can mark infected cells so that they can be swallowed and destroyed by other cells; and are called regulatory and helper T Cells of white blood cells.

In contrast, the children in the study had higher levels of the signaling proteins interferon-γ (interferon-γ) and interleukin-17 (interleukin-17). They alert the immune system to the arrival of pathogens.

These may be produced by cells in the respiratory tract and are involved in mediating innate immunity. Herold suspects that children have weaker adaptive immune responses because their innate responses are more effective in eliminating threats.

She believes that the adaptive response of adults is too active, which may lead to some complications of COVID-19.

The co-author of the study, Sophie Valkenburg of the University of Hong Kong, said that another study conducted by Hong Kong researchers on adults and children infected with SARS-CoV-2 also found that children’s adaptive responses, especially The adaptive response of T cells is less effective. This shows that some early events have caused this difference.

But Valkenburg believes that other factors such as reduced inflammation and more targeted adaptive responses may also be important. Researchers have found that infected children have low levels of monocytes, including inflammatory monocytes that act as a bridge between the innate and adaptive immune systems.

But these children do have higher levels of T follicular helper cells, which are important for the development of early antibody responses.

Young people and infected people

During the COVID-19 pandemic, nearly 15% of all confirmed cases in the United States were children. In the last week of August 2021, more than 22% of the weekly reported cases were children. This increase may be due to an increase in adult vaccination rates.

COVID-19: Why the immature immune system of Children is leading the way?

First responder

Since then, Herold et al. tried to measure the innate immune response of children more directly. They took nasopharyngeal swabs from people who came to the emergency department, including 12 mildly ill children and 27 adults, some of whom have died. Children have higher levels of signaling proteins, such as interferons and interleukins, and higher expression of genes encoding these proteins.

Yonker believes that a large class of immune cells that may play an important role in children is innate lymphoid cells, which are one of the first cells to detect tissue damage and secrete signal proteins, which help regulate innate and adaptive immune response.

In a study published in a preprint on July 4, Yonker et al. found that the number of innate lymphocytes in the blood of people who did not suffer from COVID-19 decreased with age, and was more pronounced in men. Low, which reflects the higher risk of serious illness among older men. Adults with severe diseases and children with symptoms also have decreased levels of these cells.

Compared with adults, children recently infected with SARS-CoV-2 have also been found to have higher levels of activated neutrophils, which are on the front line of dealing with strange invaders. Melanie Neeland, an immunologist at the Murdoch Children’s Research Institute (MCRI) in Melbourne, who led the work, said that neutrophils engulf virus particles before they have a chance to replicate. In addition, with age, their effectiveness will decrease.

The epithelial cells that line the inside of the nose can also coordinate the rapid immune response. In children, these cells are flooded with receptors that recognize molecules commonly found in pathogens. Specifically, the researchers found that the expression of the gene encoding MDA5 in children was significantly higher than that in adults. MDA5 is a receptor known to recognize SARS-CoV-2. After detecting the virus invader, these cells immediately trigger the production of interferon.

Research report co-author Roland Eils, a computational genomics scientist at the Berlin Institute of Health (Berlin Institute of Health), said that for adults, it takes two days to upgrade the virus defense system to the point where we start on day 0 in children. See the level. It is this time lag that makes the difference between children and adults.

Research on rare genetic immune diseases also pointed out that innate immunity plays a leading role in preventing respiratory pathogens (such as influenza).

Isabelle Meyts, a pediatric immunologist and doctor at the Catholic University of Leuven in Belgium, often sees children with immune diseases. When the pandemic came, she prepared a plan to protect them. Meyts said the patients she feared most were actually those with innate immune deficiencies.

So far, her hunch has been proven correct. Children with diseases that affect their adaptive immune response (such as those who do not produce antibodies or produce defective B cells and T cells) are unquestionably infected with SARS-CoV-2. Meyts said that some of those who become severely ill are children with defective innate immune responses. It is not the adaptive immune system that really helps defeat this virus.

A study of adults also found that a small number of patients with severe COVID-19 have mutations that interfere with the activity of type 1 interferon. And type 1 interferon plays a role in the innate immune response to the virus.

Another analysis also found that one in ten people infected with COVID-19 will produce antibodies that block the activity of these interferons, and this antibody increases with age in people who have not previously been infected with coronavirus.

However, overactive innate reactions can also be harmful. For example, people with Down syndrome are at greater risk of severe COVID-19. Meyts believes that this may be because their extra chromosomes contain several genes involved in type 1 interferon response. Meyts said that an interesting balance needs to be struck between initial underreaction and overreaction. It needs to be in the right place, and the timing needs to be perfect.

Some challenges

Researchers believe that it is difficult for innate immunity to explain all the effects, especially considering the correlation between it and adaptive responses.

Laura Vella, an immunologist and pediatric infectious disease researcher at the Children’s Hospital of Philadelphia in Pennsylvania, said that the idea that children’s immune tone is different seems very possible. But what exactly contributed to this difference? She believes that this may be the result of a combination of many factors.

Some researchers have suggested that exposure to other human coronaviruses for many years may mean that the adult immune system treats SARS-CoV-2 in the same way as other viruses, resulting in a less effective response. This concept is called original antigenic sin (original antigenic sin). ). In contrast, children may have a new and more refined response to a new virus.

Amy Chung, an immunologist at the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia, tested antibodies in the blood of hundreds of children and adults (including 50 people infected with SARS-CoV-2) Some evidence of this has been seen in an extensive study.

They found that adults have more cross-reactive antibodies against fragments of SARS-CoV-2 similar to other coronaviruses, while children tend to produce more extensive antibodies against all parts of the virus.

Researchers are also studying other factors that are known to worsen with age, such as the ability to control inflammation and heal damaged tissues. Vera Ignjatovic, a biochemist who studies pediatric hematology at MCRI, said that children are less likely to form blood clots, which may provide some protection.

Of course, not all children are asymptomatic or mildly infected. Some people, many of whom have underlying diseases such as chronic heart disease or cancer, will get severe pneumonia. For the “long-term COVID” epidemic, the estimates that symptoms last for several months or longer vary greatly.

A recent preprint showed that up to 14% of young people who tested positive for COVID-19 had multiple symptoms three months after diagnosis. There is also a small group of otherwise healthy children, about 3 out of every 10,000 infected persons under the age of 21, who have experienced a type called multi-system inflammatory syndrome in children (MIS- C) Diseases.

They usually respond well to the initial infection, but are admitted to the hospital about a month later with a range of symptoms, from heart failure to abdominal pain and conjunctivitis, but with minimal damage to the lungs. Vella said that this is a group of sick children.

Michael Levin, a pediatrician and infectious disease doctor at Imperial College London, believes that MIS-C may be caused by the production of too many antibodies or T cells in response to the infection. Levin said that despite hundreds of papers on the subject, what distinguishes MIS-C children from other groups of children is completely unknown.

As the pandemic continues, researchers worry that the virus may evolve in some way, hindering some parts of children’s innate protection. Some researchers have discovered that Alpha variants, which were once dominant in certain parts of the world, have evolved some tricks that enable them to suppress the body’s innate immune response.

They worry that Delta will do the same. Currently, in areas where the Delta virus is endemic, the increase in the number of children hospitalized seems to be the result of its increased infectivity at all ages, coupled with the fact that many adults have been vaccinated or have been infected with SARS-CoV-2. But the researchers are watching carefully.

Herold said that almost all viruses have developed techniques to evade the innate immune system, and COVID-19 is no exception. Now we can only pray for good luck, and the children’s innate immunity is still winning. But how long can it last? They don’t know either.

Original Search: Smriti Mallapaty. (2021) Kids and COVID: why young immune systems are still on top. Nature, 597: 166-168.

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