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Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity

Author

Listed:
  • Nikaïa Smith

    (Université Paris Cité)

  • Céline Possémé

    (Université Paris Cité)

  • Vincent Bondet

    (Université Paris Cité)

  • Jamie Sugrue

    (Trinity College Dublin)

  • Liam Townsend

    (Trinity College Dublin
    St James’s Hospital)

  • Bruno Charbit

    (Center for Translational Research)

  • Vincent Rouilly

    (Datactix)

  • Violaine Saint-André

    (Université Paris Cité
    Institut Pasteur)

  • Tom Dott

    (Center for Translational Research)

  • Andre Rodriguez Pozo

    (Université Paris Cité)

  • Nader Yatim

    (Université Paris Cité)

  • Olivier Schwartz

    (Institut Pasteur)

  • Minerva Cervantes-Gonzalez

    (AP-HP, Hôpital Bichat
    AP-HP, Hôpital Bichat
    IAME)

  • Jade Ghosn

    (AP-HP, Hôpital Bichat
    IAME)

  • Paul Bastard

    (Necker Hospital for Sick Children, AP-HP
    Necker Hospital for Sick Children
    Imagine Institute
    The Rockefeller University)

  • Jean Laurent Casanova

    (Necker Hospital for Sick Children, AP-HP
    Necker Hospital for Sick Children
    Imagine Institute
    The Rockefeller University)

  • Tali-Anne Szwebel

    (APHP)

  • Benjamin Terrier

    (APHP)

  • Niall Conlon

    (St James’s Hospital
    Trinity College Dublin)

  • Cliona O’Farrelly

    (Trinity College Dublin
    Trinity College Dublin)

  • Clíona Ní Cheallaigh

    (Trinity College Dublin
    St James’s Hospital)

  • Nollaig M. Bourke

    (Trinity College Dublin)

  • Darragh Duffy

    (Université Paris Cité
    Center for Translational Research)

Abstract

Host immunity to infection with SARS-CoV-2 is highly variable, dictating diverse clinical outcomes ranging from asymptomatic to severe disease and death. We previously reported reduced type I interferon in severe COVID-19 patients preceded clinical worsening. Further studies identified genetic mutations in loci of the TLR3- or TLR7-dependent interferon-I pathways, or neutralizing interferon-I autoantibodies as risk factors for development of COVID-19 pneumonia. Here we show in patient cohorts with different severities of COVID-19, that baseline plasma interferon α measures differ according to the immunoassay used, timing of sampling, the interferon α subtype measured, and the presence of autoantibodies. We also show a consistently reduced induction of interferon-I proteins in hospitalized COVID-19 patients upon immune stimulation, that is not associated with detectable neutralizing autoantibodies against interferon α or interferon ω. Intracellular proteomic analysis shows increased monocyte numbers in hospitalized COVID-19 patients but impaired interferon-I response after stimulation. We confirm this by ex vivo whole blood stimulation with interferon-I which induces transcriptomic responses associated with inflammation in hospitalized COVID-19 patients, that is not seen in controls or non-hospitalized moderate cases. These results may explain the dichotomy of the poor clinical response to interferon-I based treatments in late stage COVID-19, despite the importance of interferon-I in early acute infection and may guide alternative therapeutic strategies.

Suggested Citation

  • Nikaïa Smith & Céline Possémé & Vincent Bondet & Jamie Sugrue & Liam Townsend & Bruno Charbit & Vincent Rouilly & Violaine Saint-André & Tom Dott & Andre Rodriguez Pozo & Nader Yatim & Olivier Schwart, 2022. "Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34895-1
    DOI: 10.1038/s41467-022-34895-1
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    References listed on IDEAS

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    1. Carolina Lucas & Patrick Wong & Jon Klein & Tiago B. R. Castro & Julio Silva & Maria Sundaram & Mallory K. Ellingson & Tianyang Mao & Ji Eun Oh & Benjamin Israelow & Takehiro Takahashi & Maria Tokuyam, 2020. "Longitudinal analyses reveal immunological misfiring in severe COVID-19," Nature, Nature, vol. 584(7821), pages 463-469, August.
    2. Qian Zhang & Paul Bastard & Aurélie Cobat & Jean-Laurent Casanova, 2022. "Human genetic and immunological determinants of critical COVID-19 pneumonia," Nature, Nature, vol. 603(7902), pages 587-598, March.
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    2. Wei Feng & Joanne C. Beer & Qinyu Hao & Ishara S. Ariyapala & Aparna Sahajan & Andrei Komarov & Katie Cha & Mason Moua & Xiaolei Qiu & Xiaomei Xu & Shweta Iyengar & Thu Yoshimura & Rajini Nagaraj & Li, 2023. "NULISA: a proteomic liquid biopsy platform with attomolar sensitivity and high multiplexing," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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