SARS-CoV-2 induces human plasmacytoid predendritic cell diversification via UNC93B and IRAK4

  1. Fanny Onodi
  2. Lucie Bonnet-Madin
  3. Laurent Meertens
  4. Léa Karpf
  5. Justine Poirot
  6. Shen-Ying Zhang
  7. Capucine Picard
  8. Anne Puel
  9. Emmanuelle Jouanguy
  10. Qian Zhang
  11. Jérôme Le Goff
  12. Jean-Michel Molina
  13. Constance Delaugerre
  14. Jean-Laurent Casanova
  15. Ali Amara
  16. Vassili Soumelis

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Abstract

Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here we have isolated primary SARS-CoV-2 viral strains and studied their interaction with human plasmacytoid predendritic cells (pDCs), a key player in antiviral immunity. We show that pDCs are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus–induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2–induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2–induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN–dependent immunity against SARS-CoV-2 infection.

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  1. Version published to 10.1084/jem.20201387
  2. Version published to 10.1101/2020.07.10.197343v2 on bioRxiv
  3. ScreenIT

    SciScore for 10.1101/2020.07.10.197343: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Patients: The experiments involving human subjects were conducted in accordance with local, national, and international regulations and were approved by the French Ethics Committee, the French National Agency for the Safety of Medicines and Health Products, and the French Ministry of Research (protocols C10-13 and C10-16).
    Consent: Informed consent was obtained from all patients included in this study.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableThe IRAK4-deficient patient is a 5 years old female, who presented cellulitis to Staphylococcus aureus and a neutropenia from the age of 2 years and is carrying a homozygous stop-gain mutation (Q293X).
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Vero E6 cells were seeded in 96-well cell culture plate (15,000 cells/well), and incubated at 37°C with 200μl of inoculum and observed daily for cytopathogenic effects (CPE) by light microscopy.
    Vero E6
    suggested: None
    At 2, 24 and 48 hour post-inoculation, Vero cells were trypsinized and transferred to p96-well plates.
    Vero
    suggested: None
    Software and Algorithms
    SentencesResources
    Acquisition was performed on an Attune NxT Flow Cytometer (Thermo Fisher Scientific) or a LSR Fortessa (BD Biosciences), and analysis was done by using FlowJo software (Tree Star)
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Acquisitions were performed on a LSR Fortessa (BD Biosciences), and cytokine concentrations were determined using FCAP Array Software (BD Biosciences).
    BD Biosciences
    suggested: (BD Biosciences, RRID:SCR_013311)
    Statistical analysis: Statistical analyses were performed with one-way ANOVA, Kruskall Wallis’s test with Dunn’s multiple comparison post-test or Mann Whitney’s test, in Prism (GraphPad Software).
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    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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  4. Version published to 10.1101/2020.07.10.197343v1 on bioRxiv