Immune cell residency in the nasal mucosa may partially explain respiratory disease severity across the age range

  1. Konner Winkley
  2. Dithi Banerjee
  3. Todd Bradley
  4. Boryana Koseva
  5. Warren A. Cheung
  6. Rangaraj Selvarangan
  7. Tomi Pastinen
  8. Elin Grundberg

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Abstract

Previous studies focusing on the age disparity in COVID-19 severity have suggested that younger individuals mount a more robust innate immune response in the nasal mucosa after infection with SARS-CoV-2. However, it is unclear if this reflects increased immune activation or increased immune residence in the nasal mucosa. We hypothesized that immune residency in the nasal mucosa of healthy individuals may differ across the age range. We applied single-cell RNA-sequencing and measured the cellular composition and transcriptional profile of the nasal mucosa in 35 SARS-CoV-2 negative children and adults, ranging in age from 4 months to 65 years. We analyzed in total of ~ 30,000 immune and epithelial cells and found that age and immune cell proportion in the nasal mucosa are inversely correlated, with little evidence for structural changes in the transcriptional state of a given cell type across the age range. Orthogonal validation by epigenome sequencing indicate that it is especially cells of the innate immune system that underlie the age-association. Additionally, we characterize the predominate immune cell type in the nasal mucosa: a resident T cell like population with potent antiviral properties. These results demonstrate fundamental changes in the immune cell makeup of the uninfected nasal mucosa over the lifespan. The resource we generate here is an asset for future studies focusing on respiratory infection and immunization strategies.

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  1. Version published to 10.1038/s41598-021-95532-3
  2. ScreenIT

    SciScore for 10.1101/2021.02.05.21251067: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: For COVID-19 positive children, families were enrolled in the CODIEFY study approved by the Institute Review Board (IRB) at Children’s Mercy (IRB # STUDY00001317).
    Consent: Parents or legally appointed representatives of COVID-19 positive children were approached for enrollment and verbal consent within 24-48 hours of their test results, and children aged 7 years and above have given verbal informed assent.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Respiratory samples were collected using Copan
    Copan
    suggested: (Beckman Coulter Copan WASP DT: Walk-Away Specimen Processor, RRID:SCR_019623)
    Cells were cryopreserved in aliquots of at least one 1 × 106 cells by centrifuging the cells at 300 x g for 8 minutes, aspirating the supernatant, and resuspending the cell pellets in Recovery Cell Culture Freezing Medium (Thermo Fisher Cat No. 12648010).
    Thermo Fisher Cat
    suggested: None
    Following DRAGEN alignment, duplicate reads were marked with Picard tools (2019) MarkDuplicates and subsequently removed.
    Picard
    suggested: (Picard, RRID:SCR_006525)
    CpG sites were filtered to remove sites that had less than 10x coverage, overlapped ENCODE problematic regions, or overlapped sites in dbSNP as previously described (Busche et al., 2015).
    dbSNP
    suggested: (dbSNP, RRID:SCR_002338)
    These 250 genes were then input to the Metascape program (Zhou et al., 2019) using the default express analysis parameters.
    Metascape
    suggested: (Metascape, RRID:SCR_016620)
    Cell-cell interaction quantification: We quantified the interactions between different cell types in the nasal epithelia of pediatric patients using the cellphoneDB program (Efremova et al., 2020).
    cellphoneDB
    suggested: (CellPhoneDB, RRID:SCR_017054)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  3. Version published to 10.1101/2021.02.05.21251067v1 on medRxiv