Local and systemic responses to SARS-CoV-2 infection in children and adults
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Abstract
It is not fully understood why COVID-19 is typically milder in children 1–3 . Here, to examine the differences between children and adults in their response to SARS-CoV-2 infection, we analysed paediatric and adult patients with COVID-19 as well as healthy control individuals (total n = 93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In the airways of healthy paediatric individuals, we observed cells that were already in an interferon-activated state, which after SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon responses restrict viral replication and disease progression. The systemic response in children was characterized by increases in naive lymphocytes and a depletion of natural killer cells, whereas, in adults, cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signalling in early infection, and identify epithelial cell states associated with COVID-19 and age. Our matching nasal and blood data show a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were substantially reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children.
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Younger patients may be more capable of mounting the interferon-driven, anti-viral innate response critical to GTAU and developing robust adaptive immunity compared to adults and the elderly.
“Younger patients may be more capable of mounting the interferondriven, anti-viral innate response critical to GTAU and developing robust adaptive immunity compared to adults and the elderly (Kumar et al., 2018; Yoshida et al., 2022).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Yoshida et al., 2022
The Results (‘Distinct changes in children and adults’) report stronger local interferon responses in children that may provide better protection against SARS-CoV-2. The Results (‘Diverse immune repertoire in children’) suggest that greater T-cell receptor diversity could enable a faster, more efficient adaptive response. Our copy does not mention GTAU or establish that these responses are critical to it. (LLM, conf=0.85)
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Self-citationSaichi, M., Ladjemi, M. Z., Korniotis, S., Rousseau, C., Hamou, Z. A., Massenet-Regad, L., Amblard, E., Noël, F., Marie, Y., Bouteiller, D., et al. (2021) · Nature Cell Biology · doi:10.1038/s41556-021-00681-2 · Cited by 151 · see citing works
Fang, Y., Liu, H., Huang, H., Li, H., Saqi, A., Qiang, L., & Que, J. (2020) · Cell Research · doi:10.1038/s41422-020-0367-9 · Cited by 65 · see citing works
Age-related Differences in the Nasal Mucosal Immune Response to SARS-CoV-2
Koch, C. M., Prigge, A. D., Anekalla, K. R., Shukla, A., Umehara, H. C. D., Setar, L., Chavez, J., Abdala‐Valencia, H., Politanska, Y., Markov, N. S., et al. (2021) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2021-0292oc · Cited by 56 · see citing works
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Tang, X., Yang, M., Duan, Z., Liao, Z., Liu, L., Cheng, R., Fang, M., Gan, W., Liu, H., Xu, J., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.10.23.350348 · Cited by 43 · see citing works
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Pang, L., Liu, Y., Shen, M., Ye, J., Chen, R., Lan, Z., Wu, Z., Guo, Y., & Zhang, P. (2020) · Aging · doi:10.18632/aging.202136 · Cited by 20 · see citing works
Deaths from COVID ‘incredibly rare’ among children
Ledford, H. K. (2021) · Nature · doi:10.1038/d41586-021-01897-w · Cited by 20 · see citing works
Worlock, K. B., Yoshida, M., Meyer, K. B., et al. (2021) · doi:10.17504/protocols.io.btpunmnw · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Adverse effects of COVID-19 mRNA vaccines: the spike hypothesis
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Sacco, K., Castagnoli, R., Vakkilainen, S., Liu, C., Delmonte, O. M., Oguz, C., Kaplan, I. M., Alehashemi, S., Burbelo, P. D., Bhuyan, F., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-01724-3 · Cited by 247 · see citing works
Self-citationA spatially resolved atlas of the human lung characterizes a gland-associated immune niche
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Pullin, J. M., & McCarthy, D. J. (2022) · doi:10.1101/2022.05.09.490241 · Cited by 122 · see citing works
Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant
Thorne, L. G., Bouhaddou, M., Reuschl, A.-K., Zuliani-Alvarez, L., Polacco, B., Pelin, A., Batra, J., Whelan, M. V. X., Ummadi, M., Rojc, A., et al. (2021) · doi:10.1101/2021.06.06.446826 · Cited by 91 · see citing works
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- Authors
- Yoshida, M., Worlock, K. B., Huang, N., Lindeboom, R. G. H., Butler, C. R., Kumasaka, N., Dominguez Conde, C., Mamanova, L., Bolt, L., Richardson, L., Polanski, K., Madissoon, E., Barnes, J. L., Allen-Hyttinen, J., Kilich, E., Jones, B. C., de Wilton, A., Wilbrey-Clark, A., Sungnak, W., Pett, J. P., Weller, J., Prigmore, E., Yung, H., Mehta, P., Saleh, A., Saigal, A., Chu, V., Cohen, J. M., Cane, C., Iordanidou, A., Shibuya, S., Reuschl, A.-K., Herczeg, I. T., Argento, A. C., Wunderink, R. G., Smith, S. B., Poor, T. A., Gao, C. A., Dematte, J. E., NU SCRIPT Study Investigators, Budinger, G. R. S., Donnelly, H. K., Markov, N. S., Lu, Z., Reynolds, G., Haniffa, M., Bowyer, G. S., Coates, M., Clatworthy, M. R., Calero-Nieto, F. J., Göttgens, B., O’Callaghan, C., Sebire, N. J., Jolly, C., De Coppi, P., Smith, C. M., Misharin, A. V., Janes, S. M., Teichmann, S. A., Nikolić, M. Z., & Meyer, K. B.
- Affiliations
- Jikei University School of Medicine (JP)
- University College London (GB)
- Wellcome Sanger Institute (GB)
- Great Ormond Street Hospital (GB)
- European Bioinformatics Institute (GB)
- University College London Hospitals NHS Foundation Trust (GB)
- Royal Free London NHS Foundation Trust (GB)
- Northwestern University (US)
- Newcastle University (GB)
- University of Cambridge (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Corresponding author
- Nikolić, Marko Z.
- Meyer, Kerstin B.
- ORCID
- Yoshida, Masahiro
- Worlock, Kaylee B.
- Huang, Ni
- Lindeboom, Rik G. H.
- Butler, Colin R.
- Kumasaka, Natsuhiko
- Dominguez Conde, Cecilia
- Mamanova, Lira
- Bolt, Liam
- Richardson, Laura
- Polanski, Krzysztof
- Madissoon, Elo
- Barnes, Josephine L.
- Allen-Hyttinen, Jessica
- Kilich, Eliz
- Jones, Brendan C.
- Wilbrey-Clark, Anna
- Sungnak, Waradon
- Pett, J. Patrick
- Weller, Juliane
- Prigmore, Elena
- Yung, Henry
- Mehta, Puja
- Saleh, Aarash
- Saigal, Anita
- Chu, Vivian
- Cohen, Jonathan M.
- Cane, Clare
- Iordanidou, Aikaterini
- Shibuya, Soichi
- Reuschl, Ann-Kathrin
- Herczeg, Iván T.
- Argento, A. Christine
- Wunderink, Richard G.
- Smith, Sean B.
- Poor, Taylor A.
- Gao, Catherine A.
- Dematte, Jane E.
- Budinger, G. R. Scott
- Donnelly, Helen K.
- Markov, Nikolay S.
- Lu, Ziyan
- Reynolds, Gary
- Haniffa, Muzlifah
- Bowyer, Georgina S.
- Coates, Matthew
- Clatworthy, Menna R.
- Calero-Nieto, Fernando J.
- Göttgens, Berthold
- O’Callaghan, Christopher
- Sebire, Neil J.
- Jolly, Clare
- De Coppi, Paolo
- Smith, Claire M.
- Misharin, Alexander V.
- Janes, Sam M.
- Teichmann, Sarah A.
- Nikolić, Marko Z.
- Meyer, Kerstin B.
- Venue
- Nature
- Published
- 2021-12-22
- Volume
- 602
- Issue
- 7896
- Pages
- 321-327
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8828466
- OpenAlex
- W4200289086
- Cited by
- 365
- References
- 81
- Citations by year
- 2026: 56 · 2025: 67 · 2024: 80 · 2023: 86 · 2022: 67 · 2021: 9
- FWCI
- 19.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- medRxiv (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion, cc-by)
- Lirias (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo
- Apollo (cc-by)
- Funders
- CHEST Foundation
- GlaxoSmithKline
- World Health Organization
- Wellcome Trust (211276/D/18/Z, 214539/Z/18/Z, 223065, 206194, WT211276/Z/18/Z, 108079/Z/15/Z)
- Chan Zuckerberg Initiative (174169)
- Action Medical Research (GN2911)
- National Institute for Health and Care Research (CL-2015-01-002, RP-2017-08-ST2-002)
- Academy of Medical Sciences (SGL015\1021)
- University College London
- European Commission (874656, HORIZON2020)
- Rosetrees Trust (M35-F2)
- Great Ormond Street Hospital Charity
- Jikei University School of Medicine
- University College London Hospitals NHS Foundation Trust
- Swedish Orphan Biovitrum
- UK Regenerative Medicine Platform
- National Institutes of Health (UL1TR001422)
- Medical Research Council (MR/5005579/1, MC_PC_15005, MR/R015635/1, MR/K017047/1, MC_PC_17230, MC_PC_20022, MR/S005579/1)
- Biotechnology and Biological Sciences Research Council (BB/V006738/1)
- Japan Society for the Promotion of Science (174169)
- UCLH Biomedical Research Centre
- National Institute on Aging (P01AG049665)
- National Heart, Lung, and Blood Institute (R01HL153122, R01HL153312, R01HL149883, P01HL154998, T32HL076139)
- National Institute of Allergy and Infectious Diseases (U19AI135964)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- SARS-CoV-2, COVID-19 pandemic, interferon response, innate immunity, dendritic cells, interferon-stimulated genes, natural killer cells, cytotoxic T lymphocytes, naive lymphocytes, epithelial cells, age-related immune differences, viral replication, single-cell multi-omics
- MeSH terms
- COVID-19, SARS-CoV-2, Adult, Bronchi, Chicago, Dendritic Cells, Epithelial Cells, Female, Humans, Immunity, Innate, Interferons, Killer Cells, Natural, London, Male, Nasal Mucosa, T-Lymphocytes, Cytotoxic, Trachea, Cohort Studies, Disease Progression, Young Adult, Single-Cell Analysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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