Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity
Nature Communications | November 25, 2022
Smith N, Possémé C, Bondet V, Sugrue J, Townsend L, Charbit B, Rouilly V, Saint-André V, Dott T, Pozo AR, Yatim N, Schwartz O, Cervantes-Gonzalez M, Ghosn J, Bastard P, Casanova JL, Szwebel TA, Terrier B, Conlon N, O’Farrelly C, Cheallaigh CN, Bourke NM and Duffy D
Nature communications. 2022;13:7254
This study was performed using Simoa Homebrew assay(s).
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.