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

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 Schwartz, Minerva Cervantes-Gonzalez, Jade Ghosn, Paul Bastard, Jean Laurent Casanova, Tali-Anne Szwebel, Benjamin Terrier, Niall Conlon, Cliona O’Farrelly, Clíona Ní Cheallaigh, Nollaig M. Bourke and Darragh Duffy ()
Additional contact information
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
Bruno Charbit: Center for Translational Research
Vincent Rouilly: Datactix
Violaine Saint-André: Université Paris Cité
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
Jade Ghosn: AP-HP, Hôpital Bichat
Paul Bastard: Necker Hospital for Sick Children, AP-HP
Jean Laurent Casanova: Necker Hospital for Sick Children, AP-HP
Tali-Anne Szwebel: APHP
Benjamin Terrier: APHP
Niall Conlon: St James’s Hospital
Cliona O’Farrelly: Trinity College Dublin
Clíona Ní Cheallaigh: Trinity College Dublin
Nollaig M. Bourke: Trinity College Dublin
Darragh Duffy: Université Paris Cité

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34895-1

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