Immune response to SARS-CoV-2 in the nasal mucosa in children and adults

Koch, Clarissa M.; Prigge, Andrew D; Anekalla, Kishore R.; Shukla, Avani; Do-Umehara, Hanh Chi; Setar, Leah; Chavez, Jairo; Abdala‐Valencia, Hiam; Politanska, Yuliya; Markov, Nikolay S.; Hahn, G.; Heald‐Sargent, Taylor; Sanchez-Pinto, L. Nelson; Muller, William J.; Misharin, Alexander V.; Ridge, Karen M.; Coates, Bria M.

doi:10.1101/2021.01.26.21250269

Cited by 16 publications

(28 citation statements)

References 65 publications

(89 reference statements)

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“…It has been reported that in adults, expression of ACE2 is induced by interferon 40 and in response to infection 25 . In contrast, we observe no significant increase of ACE2 expression across cell types in children with COVID-19 ( Figure 1h ), consistent with recent bulk RNAseq comparisons 17 . However, we do see a difference in ACE2 expression in adults, with higher expression in acute versus post-COVID patients ( Extended Data Figure 3c ).…”

Section: Resultssupporting

confidence: 90%

“…A comparison across conditions ( Figure 2g ) showed that the interferon response in adult COVID-19 patients was higher than in children with COVID-19. As recent bulk RNAseq data suggest that interferon responses correlate with viral load, but not age 17 , we interpret this to indicate that like in adults, severe COVID-19 disease in children is associated with reduced interferon responses.…”

Section: Resultsmentioning

confidence: 55%

“…At single cell level, viral entry genes were shown to be most highly expressed in the nasal epithelium in healthy adults 14 . In children, bulk RNA sequencing analysis revealed lower ACE2 gene expression both in upper 15 and lower airways 13, 16 compared to adults, although more recent studies found no correlation with age or infection 17 .…”

Section: Introductionmentioning

confidence: 84%

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The local and systemic response to SARS-CoV-2 infection in children and adults

Yoshida¹,

Worlock²,

Huang³

et al. 2021

Preprint

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While a substantial proportion of adults infected with SARS-CoV-2 progress to develop severe disease, children rarely manifest respiratory complications. Therefore, understanding differences in the local and systemic response to SARS-CoV-2 infection between children and adults may provide important clues about the pathogenesis of SARS-CoV-2 infection. To address this, we first generated a healthy reference multi-omics single cell data set from children (n=30) in whom we have profiled triple matched samples: nasal and tracheal brushings and PBMCs, where we track the developmental changes for 42 airway and 31 blood cell populations from infancy, through childhood to adolescence. This has revealed the presence of naive B and T lymphocytes in neonates and infants with a unique gene expression signature bearing hallmarks of innate immunity. We then contrast the healthy reference with equivalent data from severe paediatric and adult COVID-19 patients (total n=27), from the same three types of samples: upper and lower airways and blood. We found striking differences: children with COVID-19 as opposed to adults had a higher proportion of innate lymphoid and non-clonally expanded naive T cells in peripheral blood, and a limited interferon-response signature. In the airway epithelium, we found the highest viral load in goblet and ciliated cells and describe a novel inflammatory epithelial cell population. These cells represent a transitional regenerative state between secretory and ciliated cells; they were found in healthy children and were enriched in pediatric and adult COVID-19 patients. Epithelial cells display an antiviral and neutrophil-recruiting gene signature that is weaker in severe paediatric versus adult COVID-19. Our matched blood and airway samples allowed us to study the spatial dynamics of infection. Lastly, we provide a user-friendly interface for this data as a highly granular reference for the study of immune responses in airways and blood in children.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 84%

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The local and systemic response to SARS-CoV-2 infection in children and adults

Yoshida¹,

Worlock²,

Huang³

et al. 2021

Preprint

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“…One study found that children with COVID-19 expressed higher levels of genes associated with innate immune pathways, including interferon-stimulated genes and genes related to NLRP3 inflammasome signaling 20 . Another study, however, found no age-related differences in interferon-stimulated gene expression and reported globally similar host transcriptional responses between adults and children with diverse types of viral infections 21 , highlighting the need for further investigation. Importantly, neither study directly controlled for SARS-CoV-2 viral load when comparing immune-related gene expression between children and adults.…”

Section: Introductionmentioning

confidence: 97%

Upper airway gene expression reveals a more robust innate and adaptive immune response to SARS-CoV-2 in children compared with older adults

Mick

Tsitsiklis

Spottiswoode

et al. 2021

Preprint

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Unlike other respiratory viruses, SARS-CoV-2 disproportionately causes severe disease in older adults and only rarely in children. To investigate whether differences in the upper airway immune response could contribute to this disparity, we compared nasopharyngeal gene expression in 83 children (<19-years-old; 38 with SARS-CoV-2, 11 with other respiratory viruses, 34 with no virus) and 154 adults (>40-years-old; 45 with SARS-CoV-2, 28 with other respiratory viruses, 81 with no virus). Expression of interferon-stimulated genes (ISGs) was robustly activated in both children and adults with SARS-CoV-2 compared to the respective non-viral groups, with only relatively subtle distinctions. Children, however, demonstrated markedly greater upregulation of pathways related to B cell and T cell activation and proinflammatory cytokine signaling, including TNF, IFNγ, IL-2 and IL-4 production. Cell type deconvolution confirmed greater recruitment of B cells, and to a lesser degree macrophages, to the upper airway of children. Only children exhibited a decrease in proportions of ciliated cells, the primary target for SARS-CoV-2, upon infection with the virus. These findings demonstrate that children elicit a more robust innate and adaptive immune response to SARS-CoV-2 infection in the upper airway that likely contributes to their protection from severe disease in the lower airway.

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“…A recent complementary study analyzed the cell composition of the nasal mucosa in healthy and SARS-CoV-2 infected children based on bulk RNA-Seq and cell deconvolution methods. They were unable to identify children-specific goblet cells, but rather described that samples from healthy children were dominated by a ciliated cell signature highlighting the limitations of bulk RNA approaches 10 .…”

mentioning

confidence: 99%

Pre-activated anti-viral innate immunity in the upper airways controls early SARS-CoV-2 infection in children

Loske

Röhmel

Lukassen

et al. 2021

Preprint

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Children are consistently reported to have reduced SARS-CoV-2 infection rates and a substantially lower risk for developing severe COVID-19. However, the molecular mechanisms underlying protection against COVID-19 in younger age groups remain widely unknown. Here, we systematically characterized the single-cell transcriptional landscape in the upper airways in SARS-CoV-2 negative and age-matched SARS-CoV-2 positive children (n=42) and corresponding samples from adults (n=44), covering an age range of four weeks to 77 years. Children displayed higher basal expression of the relevant pattern recognition receptor (PRR) pathways in upper airway epithelial cells, macrophages, and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection compared to adults. We further detected distinct immune cell subpopulations with an overall dominance of neutrophils and a population of cytotoxic T cells occurring predominantly in children. Our study provides evidence that the airway epithelial and mucosal immune cells of children are pre-activated and primed for virus sensing, resulting in a stronger early innate antiviral responses to SARS-CoV-2 infection compared to adults.

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Immune response to SARS-CoV-2 in the nasal mucosa in children and adults

Cited by 16 publications

References 65 publications

The local and systemic response to SARS-CoV-2 infection in children and adults

The local and systemic response to SARS-CoV-2 infection in children and adults

Upper airway gene expression reveals a more robust innate and adaptive immune response to SARS-CoV-2 in children compared with older adults

Pre-activated anti-viral innate immunity in the upper airways controls early SARS-CoV-2 infection in children

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