The discovery of the importance of the interferon response in the prevention of serious infections will underpin new diagnostics and treatments.
Fundamental differences in the immune response of adults and children may help explain why children are much less likely to get seriously ill SARS-CoV-2, according to new research from the Wellcome Sanger Institute, University College London and their collaborators.
The study, published in the journal Nature, is the most comprehensive single-cell study to compare SARS-CoV-2 infection in adults and children across multiple organs. The researchers found that a stronger ‘innate’ immune response in children’s airways, characterized by the rapid deployment of interferons, helped limit viral replication early on. In adults, a slower immune response meant the virus was better able to invade other parts of the body where the infection was harder to control.
As part of the Human Cell Atlas1 initiative to map every type of cell in the human body, the results will be a valuable contribution to predicting personal risk of SARS-CoV-2. A nasal swab to measure the immune response in newly infected adults could be used to identify higher-risk individuals who might be candidates for preventive monoclonal antibody therapy. Recent research has also suggested that inhaled interferons may be a viable therapy.2.
The immune system we are born with is not the same as the one we have as adults. Children’s “innate” immune system is better able to automatically recognize dangerous viruses or bacteria, triggering “naïve” B and T cells that can adapt to the threat. Adults have a more “adaptive” immune system containing a large repertoire of “memory” B and T cell types, which have been trained by past exposure to respond to a particular threat3. Although the adult immune system also has an innate response, it is more active in children.
One of the key mechanisms of both immune systems is a group of proteins called interferons, which are released in the presence of viral or bacterial threats and signal nearby cells to step up their defenses. Interferons are proteins with strong antiviral activity and their production usually leads to the activation of B and T cells, which kill infected cells and prevent the pathogen from spreading further.
For this study, researchers from University College London (UCL) and affiliated hospitals4 collected and processed paired airway and blood samples from 19 pediatric and 18 adult patients COVID-19[female[feminine patients with symptoms ranging from asymptomatic to severe, as well as control samples from 41 healthy children and adults.
Single-cell sequencing of the samples was performed at the Wellcome Sanger Institute to generate a dataset of 659,217 single cells. These cells were then analyzed, revealing 59 different cell types in the airways and 34 cell types in the blood, some of which had never been described before.
The analysis showed that interferons were more highly expressed in healthy children than in adults, with a faster immune response to infection in the children’s airways. This would help limit viral replication early on and give children an immediate advantage in preventing the virus from infecting the blood and other organs.
“Because SARS-CoV-2 is a new virus, it is not something the adaptive immune system of adults has learned to respond to. Children’s innate immune system is more flexible and better able to respond to new threats. What we see at the molecular level are high levels of interferons and a very rapid immune response in children that help explain why they are less severely affected by COVID-19 than adults.
— Dr Masahiro Yoshida, University College London
The study also detailed how the adult immune system, with its high number of “killer” immune cells such as B and T cells, can act against the body once SARS-CoV-2 has spread to other parts of a patient.
“Compared to children, adult blood contains a greater number and variety of cytotoxic immune cells, designed to kill infected cells to prevent the spread of an infection. But there is a fine line between helping and once the virus has spread to multiple areas of the body, organ damage can be caused by the immune system trying and failing to control the infection.Our study shows that not only do children respond better initially , but if the virus enters the blood, the cytotoxic response is less potent.
— Dr Marko Nikolic, University College London
Knowing exactly how and why the immune response to SARS-CoV-2 may fail to control the infection or begin to harm the body gives scientists the means to begin to ask why some people may be at higher risk of serious illness. .
These data suggest that newly diagnosed adults could be tested for airway levels of interferon. Higher levels of interferon, similar to those found in children, would suggest a lower risk of severe disease, while low levels of interferon would suggest a higher risk. High-risk patients could then be considered for preventive treatments such as monoclonal antibodies, which are expensive and may be in limited supply.
“To put it simply, the innate immune response is better at fighting COVID-19 and children have stronger innate immunity, but immunity is also a complex ballet involving many cell types. The timing and types of cells triggered will influence the development of an infection, and this will vary from individual to individual for all sorts of reasons besides age. Some of the differences we see between children and adults can help us think about how we assess personal risk for adults as a means of mitigating serious illness and death.
— Dr. Kerstin Meyer, Wellcome Sanger Institute
In addition, there is growing evidence for the therapeutic benefits of inhaled interferon beta 1a. Based on the study results, this should be especially the case for patients with weak or absent interferon activation.
“The findings are insightful not just for tackling COVID-19, but more broadly for understanding changes in the airways and blood throughout childhood. They demonstrate the power of single-cell resolution to reveal differences in the biology of children and adults, while highlighting very different considerations when thinking about how a specific disease arises and can be treated.
— Jonah Cool, Chan Zuckerberg Initiative
Remarks
- The Human Cell Atlas (HCA) is an international collaborative consortium that creates comprehensive reference maps of all human cells – the fundamental units of life – as the basis for understanding human health and for diagnosing, monitoring and treating disease . The HCA will impact all aspects of biology and medicine, propelling discoveries and translational applications and ultimately leading to a new era of precision medicine. The HCA was co-founded in 2016 by Dr Sarah Teichmann at the Wellcome Sanger Institute (UK) and Dr Aviv Regev, then at the Broad Institute of MIT and Harvard (USA). A truly global initiative, there are now over 2,000 HCA members, from over 75 countries around the world. https://www.humancellatlas.org
- For more information on these studies, see: https://pubmed.ncbi.nlm.nih.gov/33189161/
and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833737/ - This article from The Atlantic is an informative and accessible primer on the human immune system and how it responds to SARS-CoV-2.
- UCL affiliated hospitals including Great Ormond Street Hospital, University College Hospital, Royal Free Hospitals and Whittington Hospital
Reference: “Local and systemic responses to SARS-CoV-2 infection in children and adults” by Masahiro Yoshida, Kaylee B. Worlock, Ni Huang, Rik GH Lindeboom, Colin R. Butler, Natsuhiko Kumasaka, Cecilia Dominguez Conde, Lira Mamanova, Liam Bolt, Laura Richardson, Krzysztof Polanski, Elo Madisson, Josephine L. Barnes, Jessica Allen-Hyttinen, Eliz Kilich, Brendan C. Jones, Angus de Wilton, Anna Wilbrey-Clark, Waradon Sungnak, J. Patrick Pett, Juliane Weller, Elena Prigmore, Henry Yung, Puja Mehta, Aarash Saleh, Anita Saigal, Vivian Chu, Jonathan M. Cohen, Clare Cane, Aikaterini Iordanidou, Soichi Shibuya, Ann-Kathrin Reuschl, Iván T. Herczeg, A. Christine Argento, Richard G. Wunderink, Sean B. Smith, Taylor A. Poor, Catherine A. Gao, Jane E. Dematte, NU SCRIPT Study Investigators, Gary Reynolds, Muzlifah Haniffa, Georgina S. Bowyer, Matthew Coates, Menna R. Clatworthy, Fernando J. Calero-Nieto, Berthold Göttgens, Christopher O’Callaghan, Neil J. Sebire, Clare Joll y, Paolo de Coppi, Clair e M. Smith, Alexander V. Misharin, Sam M. Janes, Sarah A. Teichmann, Marko Z. Nikolic and Kerstin B. Meyer, December 22, 2021, Nature.
DOI: 10.1038/s41586-021-04345-x
This research was funded by Wellcome, the Chan Zuckerberg Initiative, Rosetrees Trust, Action Medical Research, the Medical Research Council and the European Union’s Horizon 2020 programme.