Sustained type I interferon activity and N-antigenemia form a vicious cycle during severe COVID-19.
Abstract
Background
Although 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
This 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
Across 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
These 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
Agence 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.
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BibTeX
@article{mouton2026sustained,
title = {{Sustained type I interferon activity and N-antigenemia form a vicious cycle during severe COVID-19.}},
author = {William Mouton and Kahina Saker and Priscille Franc and Marine Mommert-Tripon and Guy Oriol and Laurence Generenaz and Valérie Cheynet and Antonin Bal and Léa Pons and Brice Wittmann and David Bussy and Paul Bastard and Jean-Laurent Casanova and Sarah Sebai and Amel Chebel and Fabrice Chatonnet and Dominique Costagliola and Jose Arribas and Hans-Kittil Viermyr and Julien Poissy and Aleksander Rygh Holten and Aliou Baldé and Emmanuel Roux and Inge C. Olsen and Karen Brengel-Pesce and Sylvie Pons and Cécile Barnel and Bouchra Mokdad and Florent Wallet and Laurent Genestier and Olivier Terrier and Marius Trøseid and Jean-Christophe Richard and Sophie Trouillet-Assant and Mehdi Mezidi and Hodane Yonis and Laurent Bitker and Guillaume Deniel and Florent Wallet and Donatien De Marignan and Auguste Dargent and Marius Trøseid and José Arribas and Lambert Assoumou and Aleksander Rygh Holten and Julien Poissy and Vida Terzić and Fulvia Mazzaferri and Jesús Rodríguez Baño and Joe Eustace and Maya Hites and Michael Joannidis and José-Artur Paiva and Jean Reuter and Isabel Püntmann and Thale Patrick-Brown and Elin Westerheim and Katerina Nezvalova-Henriksen and Lydie Beniguel and Tuva Børresdatter Dahl},
journal = {EBioMedicine},
year = {2026},
month = oct,
doi = {10.1016/j.ebiom.2026.106508},
url = {https://europepmc.org/article/MED/42863370},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Sustained type I interferon activity and N-antigenemia form a vicious cycle during severe COVID-19.
AU - William Mouton
AU - Kahina Saker
AU - Priscille Franc
AU - Marine Mommert-Tripon
AU - Guy Oriol
AU - Laurence Generenaz
AU - Valérie Cheynet
AU - Antonin Bal
AU - Léa Pons
AU - Brice Wittmann
AU - David Bussy
AU - Paul Bastard
AU - Jean-Laurent Casanova
AU - Sarah Sebai
AU - Amel Chebel
AU - Fabrice Chatonnet
AU - Dominique Costagliola
AU - Jose Arribas
AU - Hans-Kittil Viermyr
AU - Julien Poissy
AU - Aleksander Rygh Holten
AU - Aliou Baldé
AU - Emmanuel Roux
AU - Inge C. Olsen
AU - Karen Brengel-Pesce
AU - Sylvie Pons
AU - Cécile Barnel
AU - Bouchra Mokdad
AU - Florent Wallet
AU - Laurent Genestier
AU - Olivier Terrier
AU - Marius Trøseid
AU - Jean-Christophe Richard
AU - Sophie Trouillet-Assant
AU - Mehdi Mezidi
AU - Hodane Yonis
AU - Laurent Bitker
AU - Guillaume Deniel
AU - Florent Wallet
AU - Donatien De Marignan
AU - Auguste Dargent
AU - Marius Trøseid
AU - José Arribas
AU - Lambert Assoumou
AU - Aleksander Rygh Holten
AU - Julien Poissy
AU - Vida Terzić
AU - Fulvia Mazzaferri
AU - Jesús Rodríguez Baño
AU - Joe Eustace
AU - Maya Hites
AU - Michael Joannidis
AU - José-Artur Paiva
AU - Jean Reuter
AU - Isabel Püntmann
AU - Thale Patrick-Brown
AU - Elin Westerheim
AU - Katerina Nezvalova-Henriksen
AU - Lydie Beniguel
AU - Tuva Børresdatter Dahl
PY - 2026
DA - 2026/10/12
JO - EBioMedicine
DO - 10.1016/j.ebiom.2026.106508
UR - https://europepmc.org/article/MED/42863370
AB - Background Although 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 This 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 Across 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 These 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 Agence 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.
SN - 2352-3964
ER -