Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

Author:

Hadjadj Jérôme12ORCID,Yatim Nader23ORCID,Barnabei Laura1,Corneau Aurélien4,Boussier Jeremy3ORCID,Smith Nikaïa3ORCID,Péré Hélène56,Charbit Bruno7ORCID,Bondet Vincent3ORCID,Chenevier-Gobeaux Camille8,Breillat Paul2ORCID,Carlier Nicolas9ORCID,Gauzit Rémy10,Morbieu Caroline2,Pène Frédéric1112ORCID,Marin Nathalie12,Roche Nicolas911ORCID,Szwebel Tali-Anne2ORCID,Merkling Sarah H.13ORCID,Treluyer Jean-Marc1415,Veyer David616,Mouthon Luc211ORCID,Blanc Catherine4,Tharaux Pierre-Louis5ORCID,Rozenberg Flore1117,Fischer Alain11819,Duffy Darragh37ORCID,Rieux-Laucat Frédéric1ORCID,Kernéis Solen102021ORCID,Terrier Benjamin25

Affiliation:

1. Université de Paris, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, F-75015 Paris, France.

2. Department of Internal Medicine, National Reference Center for Rare Systemic Autoimmune Diseases, AP-HP, APHP-CUP, Hôpital Cochin, F-75014 Paris, France.

3. Institut Pasteur, Laboratory of Dendritic Cell Immunobiology, INSERM U1223, Department of Immunology, F-75015 Paris, France.

4. Sorbonne Université, UMS037, PASS, Plateforme de cytométrie de la Pitié-Salpêtrière CyPS, F-75013 Paris, France.

5. Université de Paris, INSERM, U970, PARCC, F-75015 Paris, France.

6. Service de Microbiologie, AP-HP, APHP-CUP, Hôpital Européen Georges Pompidou, F-75015 Paris, France.

7. Institut Pasteur, Cytometry and Biomarkers UTechS, CRT, F-75015 Paris, France.

8. Department of Automated Diagnostic Biology, Hôpital Cochin, APHP, APHP-CUP, F-75014 Paris, France.

9. Department of Pulmonology, Hôpital Cochin, AP-HP, APHP-CUP, F-75014 Paris, France.

10. Equipe Mobile d’Infectiologie, Hôpital Cochin, AP-HP, APHP-CUP, F-75014 Paris, France.

11. Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, F-75006 Paris, France.

12. Service de Médecine Intensive et Réanimation, Hôpital Cochin, AP-HP, APHP-CUP, F-75014 Paris, France.

13. Institut Pasteur, Insect-Virus Interactions Unit, UMR 2000, CNRS, Paris, France.

14. Université de Paris, Pharmacologie et Evaluation des Thérapeutiques Chez l’Enfant et la Femme Enceinte EA7323, F-75006 Paris, France.

15. Recherche Clinique et Pharmacologie, AP-HP, APHP-CUP, Hôpitaux Cochin Necker, F-75014 Paris, France.

16. Université de Paris and Sorbonne Université, INSERM, Centre de Recherche des Cordeliers, Functional Genomics of Solid Tumors (FunGeST), F-75006 Paris, France.

17. Service de Virologie, Hôpital Cochin, AP-HP, APHP-CUP, F-75014 Paris, France.

18. Department of Paediatric Immuno-Haematology and Rheumatology, AP-HP, APHP.CUP, Hôpital Necker, F-75015 Paris, France.

19. Collège de France, Paris, France.

20. Université de Paris, INSERM, IAME, F-75006 Paris, France.

21. Institut Pasteur, Epidemiology and Modelling of Antibiotic Evasion (EMAE), F-75015 Paris, France.

Abstract

Interferons interfere with lung repair Interferons (IFNs) are central to antiviral immunity. Viral recognition elicits IFN production, which in turn triggers the transcription of IFN-stimulated genes (ISGs), which engage in various antiviral functions. Type I IFNs (IFN-α and IFN-β) are widely expressed and can result in immunopathology during viral infections. By contrast, type III IFN (IFN-λ) responses are primarily restricted to mucosal surfaces and are thought to confer antiviral protection without driving damaging proinflammatory responses. Accordingly, IFN-λ has been proposed as a therapeutic in coronavirus disease 2019 (COVID-19) and other such viral respiratory diseases (see the Perspective by Grajales-Reyes and Colonna). Broggi et al. report that COVID-19 patient morbidity correlates with the high expression of type I and III IFNs in the lung. Furthermore, IFN-λ secreted by dendritic cells in the lungs of mice exposed to synthetic viral RNA causes damage to the lung epithelium, which increases susceptibility to lethal bacterial superinfections. Similarly, using a mouse model of influenza infection, Major et al. found that IFN signaling (especially IFN-λ) hampers lung repair by inducing p53 and inhibiting epithelial proliferation and differentiation. Complicating this picture, Hadjadj et al. observed that peripheral blood immune cells from severe and critical COVID-19 patients have diminished type I IFN and enhanced proinflammatory interleukin-6– and tumor necrosis factor-α–fueled responses. This suggests that in contrast to local production, systemic production of IFNs may be beneficial. The results of this trio of studies suggest that the location, timing, and duration of IFN exposure are critical parameters underlying the success or failure of therapeutics for viral respiratory infections. Science , this issue p. 706 , p. 712 , p. 718 ; see also p. 626

Funder

Agence Nationale de la Recherche

Fonds Immunov

Institut Imagine

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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