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

Nikaïa Smith (1) , Céline Possémé (1) , Vincent Bondet (1) , Jamie Sugrue (2) , Liam Townsend (2, 3) , Bruno Charbit (4) , Vincent Rouilly (5) , Violaine Saint-André (1, 6) , Tom Dott (4) , Andre Rodriguez Pozo (1) , Nader Yatim (1) , Olivier Schwartz (7) , Minerva Cervantes-Gonzalez (8, 9) , Jade Ghosn (8, 9) , Paul Bastard (10, 11, 12) , Jean Laurent Casanova (10, 11, 12, 13) , Tali-Anne Szwebel (14) , Benjamin Terrier (14) , Niall Conlon (3, 2) , Cliona O’Farrelly (2) , Clíona Ní Cheallaigh (2, 3) , Nollaig M. Bourke (2) , Darragh Duffy (1, 4)

1 Immunologie Translationnelle - Translational Immunology lab
2 Trinity College Dublin
3 SJH - Saint James Hospital
4 CRT - Centre de Recherche Translationnelle - Center for Translational Science
5 Datactix
6 Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB
7 CNRS-UMR3569 - Virus et Immunité - Virus and immunity
8 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
9 IAME (UMR_S_1137 / U1137) - Infection, Anti-microbiens, Modélisation, Evolution
10 CHU Necker - Enfants Malades [AP-HP]
11 Equipe Inserm U1163 - Human genetics of infectious diseases : Mendelian predisposition
12 Rockefeller University [New York]
13 HHMI - Howard Hughes Medical Institute
14 IC UM3 (UMR 8104 / U1016) - Institut Cochin

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.

Domains: Life Sciences [q-bio]

Nikaïa Smith, Céline Possémé, Vincent Bondet, Jamie Sugrue, Liam Townsend, et al.. Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity. Nature Communications, 2022, 13 (1), pp.7254. ⟨10.1038/s41467-022-34895-1⟩. ⟨pasteur-03884236⟩