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

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 mutat...

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Detalles Bibliográficos
Autores principales: Smith, Nikaïa, Possémé, Céline, Bondet, Vincent, Sugrue, Jamie, Townsend, Liam, Charbit, Bruno, Rouilly, Vincent, Saint-André, Violaine, Dott, Tom, Pozo, Andre Rodriguez, Yatim, Nader, Schwartz, Olivier, Cervantes-Gonzalez, Minerva, Ghosn, Jade, Bastard, Paul, Casanova, Jean Laurent, Szwebel, Tali-Anne, Terrier, Benjamin, Conlon, Niall, O’Farrelly, Cliona, Cheallaigh, Clíona Ní, Bourke, Nollaig M., Duffy, Darragh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9700809/
https://www.ncbi.nlm.nih.gov/pubmed/36434007
http://dx.doi.org/10.1038/s41467-022-34895-1
Descripción
Sumario: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.