Why do children and adolescents experience severe outcomes from SARS-CoV-2 infection much less frequently than adults? Scientists from the DZL and the German Cancer Consortium (DKTK) have now discovered that the immune system in the upper respiratory tract of children is significantly more active before infection than in adults, making it better prepared to fight the virus.
Many risk factors for severe outcomes of SARS-CoV-2 infection are known, including high blood pressure, diabetes, obesity, or pre-existing heart conditions. However, the most obvious and striking risk factor for severe outcomes is age. During the pandemic, fewer than 0.001 percent of infected schoolchildren died from the infection. As age increased, the mortality rate rose almost exponentially, reaching over 10 percent in very elderly individuals. Children and adolescents exhibit fewer symptoms and a shorter duration of illness than adults, especially older adults, although the initial viral load does not differ significantly.
A crucial step toward understanding the reasons for this remarkable resistance of children to severe COVID-19 illness was achieved by DZL researchers at the Berlin Institute of Health (BIH) in Charité, Berlin, and the DKFZ in 2022. They found that the epithelial cells of the nasal mucosa in healthy children are permanently in a state of "heightened alertness." The molecular background: The sensor proteins that recognize the virus by its RNA and initiate an interferon response are much more pronounced in the cells of the nasal mucosa in children than in adults. As a result, once the virus enters the cell, it can be quickly recognized and combated.
But why is the nasal mucosa of children so much better prepared to defend against SARS-CoV-2? To answer this question, Marco Binder and his team at the DKFZ, together with colleagues in Berlin, conducted a more detailed examination of the cellular composition of the nasal mucosa in the nasal cavity of healthy children at the level of individual cells.
The main result of the virologists: Compared to adults, the nasal mucosa of children is not only inhabited by significantly more immune cells. In addition, even in healthy, non-infected children, individual immune cells produce more pro-inflammatory messenger substances, known as cytokines. Through these messenger substances, the immune system communicates with the mucosal cells, stimulating them to produce the sensor proteins.
"We have shown that the presence of low doses of these cytokines keeps the respiratory epithelial cells in a state of heightened alertness. The mucosal cells then prepare themselves by ramping up the production of virus sensor proteins, allowing them to react much faster to SARS-CoV-2 infection."
Thus, children apparently have an innate strong protective mechanism against respiratory infections, which likely also applies to the defense against other viruses. "During the pandemic, this difference was particularly pronounced because the immune system of all people came into contact with this coronavirus for the very first time," explains Binder. "With other infections such as colds or flu, adults have already built up an immune memory through repeated contact with the viruses, which helps in defending against the pathogens. As a result, the effectiveness of children's superior virus defense may not be as pronounced."
And another peculiar feature mentioned by the virologist: "SARS-CoV-2 replicates extremely rapidly in our cells and also has many tricks up its sleeve to disable the sensors of the cellular virus alarm system. Therefore, the child's protective mechanism is particularly important for this pathogen. In other respiratory infections, the difference between children and adults may not be as dramatic." This is a question the scientist intends to pursue in future research projects.
Binder believes it may be worthwhile to explore prophylactic strategies for SARS-CoV-2 and other respiratory infections. "Such approaches could aim to mimic the cellular composition of mucosal tissue in children, for example, by inhaling low-dose cytokine preparations."
Original publication:
Vladimir G. Magalhaes, Soren Lukassen, Maike Drechsler, Jennifer Loske, Sandy S. Burkart, Sandra Wust, Eva-Maria Jacobsen, Jobst Rohmel, Marcus A. Mall, Klaus-Michael Debatin, Roland Eils, Stella Autenrieth1, Aleš Janda, Irina Lehmann, Marco Binder:
Immune–Epithelial Cell Cross-Talk Enhances Antiviral Responsiveness to SARS CoV-2 in Children
EMBO Reports 2023, DOI: 10.15252/embr.202357912
The German Cancer Research Center (DKFZ) with more than 3,000 employees is the largest biomedical research institution in Germany. Scientists at DKFZ investigate how cancer develops, identify cancer risk factors, and search for new strategies to prevent people from developing cancer. They develop new methods for more precise diagnosis of tumors and more successful treatment of cancer patients. The Cancer Information Service (KID) at DKFZ provides individual answers to all questions about cancer for those affected, interested parties, and professionals.
To translate promising approaches from cancer research into clinical practice and thus improve the chances of patients, DKFZ operates translational centers in collaboration with excellent university hospitals and research institutions throughout Germany:
National Center for Tumor Diseases (NCT, 6 locations)
German Consortium for Translational Cancer Research (DKTK, 8 locations)
Hopp Children's Tumor Center (KiTZ) Heidelberg
Helmholtz Institute for Translational Oncology (HI-TRON) Mainz – a Helmholtz Institute of DKFZ
DKFZ Hector Cancer Institute at University Medical Center Mannheim
National Cancer Prevention Center (in collaboration with the German Cancer Aid)
