Upper airway gene expression shows a more robust adaptive immune response to SARS-CoV-2 in children

  1. Eran Mick
  2. Alexandra Tsitsiklis
  3. Natasha Spottiswoode
  4. Saharai Caldera
  5. Paula Hayakawa Serpa
  6. Angela M. Detweiler
  7. Norma Neff
  8. Angela Oliveira Pisco
  9. Lucy M. Li
  10. Hanna Retallack
  11. Kalani Ratnasiri
  12. Kayla M. Williamson
  13. Victoria Soesanto
  14. Eric A. F. Simões
  15. Christiana Smith
  16. Lisa Abuogi
  17. Amy Kistler
  18. Brandie D. Wagner
  19. Joseph L. DeRisi
  20. Lilliam Ambroggio
  21. Peter M. Mourani
  22. Charles R. Langelier

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Abstract

Unlike other respiratory viruses, SARS-CoV-2 disproportionately causes severe disease in older adults whereas disease burden in children is lower. To investigate whether differences in the upper airway immune response may contribute to this disparity, we compare 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 older adults (>40-years-old; 45 with SARS-CoV-2, 28 with other respiratory viruses, 81 with no virus). Expression of interferon-stimulated genes is robustly activated in both children and adults with SARS-CoV-2 infection compared to the respective non-viral groups, with only subtle distinctions. Children, however, demonstrate markedly greater upregulation of pathways related to B cell and T cell activation and proinflammatory cytokine signaling, including response to TNF and production of IFNγ, IL-2 and IL-4. Cell type deconvolution confirms greater recruitment of B cells, and to a lesser degree macrophages, to the upper airway of children. Only children exhibit a decrease in proportions of ciliated cells, among the primary targets of SARS-CoV-2, upon infection. These findings demonstrate that children elicit a more robust innate and especially adaptive immune response to SARS-CoV-2 in the upper airway that likely contributes to their protection from severe disease in the lower airway.

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  1. Version published to 10.1038/s41467-022-31600-0
  2. Version published to 10.21203/rs.3.rs-784784/v1 on Research Square
  3. ScreenIT

    SciScore for 10.1101/2021.07.15.21260285: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The UCSF Institutional Review Board (IRB) granted a waiver of consent under IRB protocol #17-24056.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    We also processed negative control samples (water and HeLa cell RNA) to account for background contamination.
    HeLa
    suggested: CLS Cat# 300194/p772_HeLa, RRID:CVCL_0030)
    Software and Algorithms
    SentencesResources
    Metagenomic analysis of respiratory viruses: Samples were processed through the IDSeq pipeline36,37, which performs reference based alignment at both the nucleotide and amino acid level against sequences in the National Center for Biotechnology Information (NCBI) nucleotide (NT) and non-redundant (NR) databases, respectively, followed by assembly of the reads matching each taxon detected.
    IDSeq
    suggested: (IDseq, RRID:SCR_019038)
    Human gene expression quantification: Following demultiplexing, sequencing reads were pseudo-aligned with kallisto39 (v. 0.46.1; including bias correction) to an index consisting of all transcripts associated with human protein coding genes (ENSEMBL v.99), cytosolic and mitochondrial ribosomal RNA sequences, and the sequences of ERCC RNA standards.
    ENSEMBL
    suggested: (Ensembl, RRID:SCR_002344)
    The design formula for the direct comparison between children and adults with SARS-CoV-2 was ∼log10(rpM) + age cohort, where age cohort was either “children” or “adults”.
    SARS-CoV-2
    suggested: (BioLegend Cat# 944703, RRID:AB_2890874)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our study has several limitations that should be kept in mind: 1) a larger sample size would have increased the generalizability of our findings; 2) we could not directly control for timing since onset of infection; 3) proteomic measurements may have provided additional insight but were not possible from the available swab specimens, which were collected into a virus inactivating agent; 4) our findings regarding tissue cellular composition require validation by single-cell sequencing; and lastly, 5) the majority of subjects with COVID-19 had mild disease at the time of sampling and did not require hospitalization. Results may have differed if specimens from a greater proportion of severely ill individuals had been available, however, this likely resulted in a more relevant comparison since few children develop severe disease. Taken together, our findings suggest children elicit a more robust pro-inflammatory and adaptive immune response to SARS-CoV-2 infection in the upper airway compared to adults but an overall comparable type I interferon response. Children, unlike adults, also display decreased proportions of ciliated cells, the primary targets of SARS-CoV-2, upon infection with the virus. These differences in the upper airway immune response and tissue composition may both contribute to the protection of children from severe disease in the lower respiratory tract. Further study is warranted to unravel why children are better protected specifically against SARS-CoV-2, or ...

    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.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  4. Version published to 10.1101/2021.07.15.21260285v1 on medRxiv