High-resolution epigenome analysis in nasal samples derived from children with respiratory viral infections reveals striking changes upon SARS-CoV-2 infection

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

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Abstract

Background

DNA methylation patterns of the human genome can be modified by environmental stimuli and provide dense information on gene regulatory circuitries. We studied genome-wide DNA methylation in nasal samples from infants (<6 months) applying whole-genome bisulfite sequencing (WGBS) to characterize epigenome response to 10 different respiratory viral infections including SARS-CoV-2.

Results

We identified virus-specific differentially methylated regions (vDMR) with human metapneumovirus (hMPV) and SARS-CoV-2 followed by Influenza B (Flu B) causing the weakest vs. strongest epigenome response with 496 vs. 78541 and 14361 vDMR, respectively. We found a strong replication rate of FluB (52%) and SARS-CoV-2 (42%) vDMR in independent samples indicating robust epigenome perturbation upon infection. Among the FluB and SARS-CoV-2 vDMRs, around 70% were hypomethylated and significantly enriched among epithelial cell-specific regulatory elements whereas the hypermethylated vDMRs for these viruses mapped more frequently to immune cell regulatory elements, especially those of the myeloid lineage. The hypermethylated vDMRs were also enriched among genes and genetic loci in monocyte activation pathways and monocyte count. Finally, we perform single-cell RNA-sequencing characterization of nasal mucosa in response to these two viruses to functionally analyze the epigenome perturbations. Which supports the trends we identified in methylation data and highlights and important role for monocytes.

Conclusions

All together, we find evidence indicating genetic predisposition to innate immune response upon a respiratory viral infection. Our genome-wide monitoring of infant viral response provides first catalogue of associated host regulatory elements. Assessing epigenetic variation in individual patients may reveal evidence for viral triggers of childhood disease.

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    SciScore for 10.1101/2021.03.09.21253155: (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
    : Transcription factor binding site (TFBS) motif analysis was performed using the Homer software (HOMER findMotifsGenome.pl v4.11.1) (Burger et al. 2013) using the central 200bp of regions.
    HOMER
    suggested: (HOMER, RRID:SCR_010881)
    The cell pellet was resuspended in 1 mL of cold Recovery Cell Culture Freezing Medium (Thermo Fisher Cat No. 12648010), and the cell suspension was transferred to a cryogenic storage vial.
    Thermo Fisher Cat
    suggested: None
    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.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2021.03.09.21253155v1 on medRxiv