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

Loske, Jennifer; Röhmel, Jobst; Lukassen, Soeren; Stricker, Sebastian; Magalhães, Vladimir Gonçalves; Liebig, Johannes; Chua, Robert Lorenz; Thürmann, Loreen; Messingschlager, Marey; Seegebarth, Anke; Timmermann, Bernd; Klages, Sven; Ralser, Markus; Sawitzki, Birgit; Sander, Leif Erik; Corman, Victor M.; Conrad, Christian; Laudi, Sven; Binder, Marco; Trump, Saskia; Eils, Roland; Mall, Marcus; Lehmann, Irina

doi:10.1101/2021.06.24.21259087

Cited by 12 publications

(17 citation statements)

References 51 publications

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“…Similarly, in the nasal fluid of children and adults presenting to the emergency department with SARS-CoV-2 there were significantly higher levels of IFN- α 2 in the fluid derived from children. Increased interferon signaling was also recorded in the nasopharyngeal transcriptome of children compared to that of adults during early SARS-CoV-2 infection [6, 46].…”

Section: Discussionmentioning

confidence: 99%

Pediatric nasal epithelial cells are less permissive to SARS-CoV-2 replication compared to adult cells

Zhu

Chew

et al. 2021

Preprint

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Rationale: Young children (typically those <10 years old) are less susceptible to SARS-CoV-2 infection and symptoms compared to adults. However, the mechanisms that underlie these age-dependent differences remain to be determined and could inform future therapeutics for adults. Objective: To contrast the infection dynamics of SARS-CoV-2 in primary nasal epithelial cells from adults and children. Methods: Viral replication was quantified by plaque assay. The cellular transcriptome of infected and uninfected cells was assessed by RNA-seq. ACE2 and TMPRSS2 protein expression were quantified by Western Blot Measurements and Main Results: We report significantly higher SARS-CoV-2 replication in adult compared to pediatric nasal epithelial cells. This was restricted to SARS-CoV-2 infection, as the same phenomenon was not observed with influenza virus infection. The differentiational SARS-CoV-2 replication dynamics were associated with an elevated type I and III interferon response, and a more pronounced inflammatory response in pediatric cells. No significant difference between the two age groups was observed in the protein levels of ACE2 and TMPRSS2. Conclusions: Our data suggest that the innate immune response of pediatric nasal epithelial cells, and not differential receptor expression, may contribute to the reported reduced SARS-COV-2 infection and symptoms reported amongst children.

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Section: Discussionmentioning

confidence: 99%

Pediatric nasal epithelial cells are less permissive to SARS-CoV-2 replication compared to adult cells

Zhu

Chew

et al. 2021

Preprint

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“…After stringent quality control, 36,406 cells were subjected to further analysis. Unsupervised clustering by UMAP identified 18 cell subtypes (Figure 4A) based on representative marker genes from previous studies (Chua et al, 2020;Loske et al, 2022). The cell populations identified by cell lineage-specific marker gene expression are shown in Supplementary File 1: Supplementary Figures S2B, C.…”

Section: Single-cell Transcriptomic Analysis Revealed High Slc40a1-ex...mentioning

confidence: 99%

“…Genes with adjusted p < 0.05 were considered as DEGs. The cell subsets were annotated based on the DEGs and known markers from the literature (Chua et al, 2020;Mould et al, 2021;Loske et al, 2022). For subclustering analysis, we applied a similar procedure, including variable gene identification, dimensionality reduction, and clustering identification, to the cluster derived from overall analysis.…”

Section: Cell Clustering and Annotationmentioning

confidence: 99%

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Transcriptomic analysis identified SLC40A1 as a key iron metabolism-related gene in airway macrophages in childhood allergic asthma

Wang

Cun

et al. 2023

Front. Cell Dev. Biol.

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Introduction: Asthma is the most common chronic condition in children, with allergic asthma being the most common phenotype, accounting for approximately 80% of cases. Growing evidence suggests that disruption of iron homeostasis and iron regulatory molecules may be associated with childhood allergic asthma. However, the underlying molecular mechanism remains unclear.Methods: Three childhood asthma gene expression datasets were analyzed to detect aberrant expression profiles of iron metabolism-related genes in the airways of children with allergic asthma. Common iron metabolism-related differentially expressed genes (DEGs) across the three datasets were identified and were subjected to functional enrichment analysis. Possible correlations between key iron metabolism-related DEGs and type 2 airway inflammatory genes were investigated. Single-cell transcriptome analysis further identified major airway cell subpopulations driving key gene expression. Key iron metabolism-related gene SLC40A1 was validated in bronchoalveolar lavage (BAL) cells from childhood asthmatics with control individuals by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunofluorescence. The intracellular iron content in BAL cells was assessed by Perls iron staining and the iron levels in BAL supernatant was measured by iron assay to assess airway iron metabolism status in childhood asthmatics.Results: Five common iron metabolism-related DEGs were identified, which were functionally related to iron homeostasis. Among these genes, downregulated SLC40A1 was strongly correlated with type 2 airway inflammatory markers and the gene signature of SLC40A1 could potentially be used to determine type 2-high and type 2-low subsets in childhood allergic asthmatics. Further single-cell transcriptomic analysis identified airway macrophages driving SLC40A1 expression. Immunofluorescence staining revealed colocalization of FPN (encoded by SLC40A1) and macrophage marker CD68. Down-regulation of SLC40A1 (FPN) was validated by qRT-PCR and immunofluorescence analysis. Results further indicated reduced iron levels in the BAL fluid, but increased iron accumulation in BAL cells in childhood allergic asthma patients. Furthermore, decreased expression of SLC40A1 was closely correlated with reduced iron levels in the airways of children with allergic asthma.Discussion: Overall, these findings reveal the potential role of the iron metabolism-related gene SLC40A1 in the pathogenesis of childhood allergic asthma.

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“…On the other hand, these specific T cell responses, mainly featuring CD8+ T cells, are affected by the altered recognition of SARS-CoV-2 by the MDA5-IFNAR1 signalling pathways (211). Airway epithelial cells from children appear to show an increased expression of MDA5 compared to its expression level in SARS-CoV-2 positive adult epithelial cells (212). Consistent with this, we found several studies showing that children eliminate SARS-CoV-2 faster than adults, probably by detaining viral replication earlier (213)(214)(215)(216).…”

Section: Balance Between Innate and Adaptive Immunitymentioning

confidence: 99%

The Robustness of Cellular Immunity Determines the Fate of SARS-CoV-2 Infection

2022

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Two years after the appearance of the SARS-CoV-2 virus, the causal agent of the current global pandemic, it is time to analyze the evolution of the immune protection that infection and vaccination provide. Cellular immunity plays an important role in limiting disease severity and the resolution of infection. The early appearance, breadth and magnitude of SARS-CoV-2 specific T cell response has been correlated with disease severity and it has been thought that T cell responses may be sufficient to clear infection with minimal disease in COVID-19 patients with X-linked or autosomal recessive agammaglobulinemia. However, our knowledge of the phenotypic and functional diversity of CD8+ cytotoxic lymphocytes, CD4+ T helper cells, mucosal-associated invariant T (MAIT) cells and CD4+ T follicular helper (Tfh), which play a critical role in infection control as well as long-term protection, is still evolving. It has been described how CD8+ cytotoxic lymphocytes interrupt viral replication by secreting antiviral cytokines (IFN-γ and TNF-α) and directly killing infected cells, negatively correlating with stages of disease progression. In addition, CD4+ T helper cells have been reported to be key pieces, leading, coordinating and ultimately regulating antiviral immunity. For instance, in some more severe COVID-19 cases a dysregulated CD4+ T cell signature may contribute to the greater production of pro-inflammatory cytokines responsible for pathogenic inflammation. Here we discuss how cellular immunity is the axis around which the rest of the immune system components revolve, since it orchestrates and leads antiviral response by regulating the inflammatory cascade and, as a consequence, the innate immune system, as well as promoting a correct humoral response through CD4+ Tfh cells. This review also analyses the critical role of cellular immunity in modulating the development of high-affinity neutralizing antibodies and germinal center B cell differentiation in memory and long-lived antibody secreting cells. Finally, since there is currently a high percentage of vaccinated population and, in some cases, vaccine booster doses are even being administered in certain countries, we have also summarized newer approaches to long-lasting protective immunity and the cross-protection of cellular immune response against SARS-CoV-2.

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

Cited by 12 publications

References 51 publications

Pediatric nasal epithelial cells are less permissive to SARS-CoV-2 replication compared to adult cells

Pediatric nasal epithelial cells are less permissive to SARS-CoV-2 replication compared to adult cells

Transcriptomic analysis identified SLC40A1 as a key iron metabolism-related gene in airway macrophages in childhood allergic asthma

The Robustness of Cellular Immunity Determines the Fate of SARS-CoV-2 Infection

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