{
  "abstract": "Background\n\nAlthough antigenemia is associated with poor outcomes in respiratory viral infections, the underlying mechanisms driving viral bloodstream dissemination remain not fully understood. Herein, we aimed to characterise SARS-CoV-2 nucleocapsid (N)-antigenemia kinetics in patients with severe COVID-19. We also sought to identify host and viral determinants associated with viral dissemination through a multiparametric integrated analysis and assess the associated risk of death.Methods\n\nThis observational study included hospitalised patients with severe COVID-19 across three independent cohorts (discovery, n = 66; confirmation, n = 137; validation, n = 27), used respectively for identification, replication, and validation of findings, along with patients with mild COVID-19 and with severe influenza infection, as a disease severity and non-COVID-19 control group. From blood and nasal samples, N-antigenemia levels were analysed in relation to 45 host/viral parameters. Multivariable logistic regression was performed to assess the association with in-hospital mortality. Single-cell RNA sequencing was used to identify host determinants, and in vitro primary human airway epithelial models were used to assess epithelial barrier integrity and viral translocation.Findings\n\nAcross cohorts, we observed a significantly higher detection rate and concentration of N-antigenemia in patients with severe COVID-19 at admission compared to those with mild COVID-19 or controls (fold change [FC] >54.7, p < 0.001 [Kruskal-Wallis, Dunn post-hoc]). Type-I interferon (IFN-I) activity was the strongest correlate of N-antigenemia (ρ = 0.72, p.adj < 0.001 [Spearman, Benjamini-Hochberg]), and longitudinal analyses revealed a strong positive sigmoidal relationship (p < 0.001 [approximate Wald test]). Patients with severe COVID-19 with neutralising autoantibodies against IFN-I lacked detectable N-antigenemia, further supporting a link between systemic viral dissemination and IFN-I activity. Single-cell RNA sequencing showed higher expression of interferon-stimulated genes in monocytes and dendritic cells in patients with a high N-antigenemia level. Furthermore, high N-antigenemia at hospital admission was independently associated with an increased risk of death (aOR 2.6, 95% CI 1.0-6.7; p = 0.042 [Wald test]). Finally, we demonstrated that prolonged IFN-I exposure in vitro appears to impair epithelial barrier integrity.Interpretation\n\nThese findings suggest that sustained IFN-I activity is associated with systemic viral dissemination and epithelial barrier dysfunction in patient with severe COVID-19. The concordance between clinical observations and in vitro data supports a potential link between prolonged IFN-I responses and these processes, although causality remains to be established. These results highlight the potential importance of the timing and duration of IFN-I immunity and warrant further investigation of its clinical relevance.Funding\n\nAgence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), ANRS Maladies Infectieuses Émergentes (ANRS MIE), Agence Nationale de la Recherche (ANR), Institut National de la Santé et de la Recherche Médicale (INSERM), European Union Horizon 2020 Research and Innovation Programme, CAPNET, and Klinbeforsk.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 467,
  "authors": [
    {
      "name": "William Mouton",
      "orcid": "0000-0002-8455-0952"
    },
    {
      "name": "Kahina Saker"
    },
    {
      "name": "Priscille Franc"
    },
    {
      "name": "Marine Mommert-Tripon"
    },
    {
      "name": "Guy Oriol"
    },
    {
      "name": "Laurence Generenaz"
    },
    {
      "name": "Valérie Cheynet"
    },
    {
      "name": "Antonin Bal"
    },
    {
      "name": "Léa Pons"
    },
    {
      "name": "Brice Wittmann"
    },
    {
      "name": "David Bussy",
      "orcid": "0009-0007-4037-2270"
    },
    {
      "name": "Paul Bastard"
    },
    {
      "name": "Jean-Laurent Casanova"
    },
    {
      "name": "Sarah Sebai"
    },
    {
      "name": "Amel Chebel"
    },
    {
      "name": "Fabrice Chatonnet"
    },
    {
      "name": "Dominique Costagliola",
      "orcid": "0000-0003-0765-0869"
    },
    {
      "name": "Jose Arribas"
    },
    {
      "name": "Hans-Kittil Viermyr",
      "orcid": "0009-0005-6268-4780"
    },
    {
      "name": "Julien Poissy"
    },
    {
      "name": "Aleksander Rygh Holten"
    },
    {
      "name": "Aliou Baldé",
      "orcid": "0000-0001-5956-698X"
    },
    {
      "name": "Emmanuel Roux"
    },
    {
      "name": "Inge C. Olsen"
    },
    {
      "name": "Karen Brengel-Pesce"
    },
    {
      "name": "Sylvie Pons"
    },
    {
      "name": "Cécile Barnel"
    },
    {
      "name": "Bouchra Mokdad"
    },
    {
      "name": "Florent Wallet"
    },
    {
      "name": "Laurent Genestier"
    },
    {
      "name": "Olivier Terrier",
      "orcid": "0000-0001-9393-7684"
    },
    {
      "name": "Marius Trøseid"
    },
    {
      "name": "Jean-Christophe Richard"
    },
    {
      "name": "Sophie Trouillet-Assant",
      "orcid": "0000-0001-6439-4705"
    },
    {
      "name": "Mehdi Mezidi"
    },
    {
      "name": "Hodane Yonis"
    },
    {
      "name": "Laurent Bitker"
    },
    {
      "name": "Guillaume Deniel"
    },
    {
      "name": "Florent Wallet"
    },
    {
      "name": "Donatien De Marignan"
    },
    {
      "name": "Auguste Dargent"
    },
    {
      "name": "Marius Trøseid"
    },
    {
      "name": "José Arribas"
    },
    {
      "name": "Lambert Assoumou"
    },
    {
      "name": "Aleksander Rygh Holten"
    },
    {
      "name": "Julien Poissy"
    },
    {
      "name": "Vida Terzić"
    },
    {
      "name": "Fulvia Mazzaferri"
    },
    {
      "name": "Jesús Rodríguez Baño"
    },
    {
      "name": "Joe Eustace"
    },
    {
      "name": "Maya Hites"
    },
    {
      "name": "Michael Joannidis"
    },
    {
      "name": "José-Artur Paiva"
    },
    {
      "name": "Jean Reuter"
    },
    {
      "name": "Isabel Püntmann"
    },
    {
      "name": "Thale Patrick-Brown"
    },
    {
      "name": "Elin Westerheim"
    },
    {
      "name": "Katerina Nezvalova-Henriksen"
    },
    {
      "name": "Lydie Beniguel"
    },
    {
      "name": "Tuva Børresdatter Dahl"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/b8fts2hmjmv6r.bib",
  "cited_by": 0,
  "doi": "10.1016/j.ebiom.2026.106508",
  "fulltext_url": "https://europepmc.org/articles/PMC13682480",
  "id": "b8fts2hmjmv6r",
  "issns": [
    "2352-3964"
  ],
  "landing_url": "https://europepmc.org/article/MED/42863370",
  "language": "eng",
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2403|interferon and immune responses"
    ]
  ],
  "openalex": "W7221572175",
  "pdf_url": "https://europepmc.org/articles/PMC13682480?pdf=render",
  "pmcid": "PMC13682480",
  "pmid": "42863370",
  "published": "2026-10-12",
  "publisher": "Elsevier BV",
  "ris": "https://research.draconitic.com/paper/b8fts2hmjmv6r.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:00Z",
      "native_id": "MED:42863370",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42863370"
    },
    {
      "first_seen": "2026-10-30T12:19:49Z",
      "native_id": "10.1016/j.ebiom.2026.106508",
      "source": "crossref",
      "url": "https://linkinghub.elsevier.com/retrieve/pii/S2352396426003920"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|interferon and immune responses",
      "subfield": "immunology"
    }
  ],
  "title": "Sustained type I interferon activity and N-antigenemia form a vicious cycle during severe COVID-19.",
  "title_text": "Sustained type I interferon activity and N-antigenemia form a vicious cycle during severe COVID-19.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:49Z",
  "url": "https://research.draconitic.com/paper/b8fts2hmjmv6r",
  "venue": "EBioMedicine",
  "versions": []
}