Severe COVID-19 is associated with hyperactivation of the alternative complement pathway - 03/02/22

Doi : 10.1016/j.jaci.2021.11.004

Jeremy Boussier, PhD ^a, Nader Yatim, MD, PhD ^b,^c, Armance Marchal, MD ^d, Jérôme Hadjadj, MD, PhD ^b,^e, Bruno Charbit, MSc ^f, Carine El Sissy, MD ^d, Nicolas Carlier, MD ^g, Frédéric Pène, MD, PhD ^h,ⁱ, Luc Mouthon, MD, PhD ^b,ⁱ, Pierre-Louis Tharaux, MD, PhD ^j, Anne Bergeron, MD, PhD ^k, David M. Smadja, MD, PhD ^l,^m,ⁿ, Frédéric Rieux-Laucat, PhD ^e, Darragh Duffy, PhD ^c,^f, Solen Kernéis, MD PhD ^o,^p, Véronique Frémeaux-Bacchi, MD, PhD ^d, Benjamin Terrier, MD, PhD ^b,^j,^⁎
^a Sorbonne Université, AP-HP Hôpital Saint-Antoine, Paris, France
^b Department of Internal Medicine, National Reference Center for Rare Systemic Autoimmune Diseases, AP-HP Hôpital Cochin, Paris, France
^c Translational Immunology Lab, Department of Immunology, Institut Pasteur, Paris, France
^d Laboratory of Immunology, AP-HP Hôpital Européen Georges Pompidou, Paris, France
^e Université de Paris, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut national de la santé et de la recherche médicale (Inserm) U1163, Institut Imagine, Paris, France
^f Cytometry and Biomarkers UTechS, CRT, Institut Pasteur, Paris, France
^g Department of Pulmonology, AP-HP Hôpital Cochin, Paris, France
^h Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR 8104, Paris, France
ⁱ Service de Médecine Intensive et Réanimation, AP-HP Hôpital Cochin, Paris, France
^j Université de Paris, Paris Cardiovascular Center (PARCC), Inserm, Paris, France
^k Université de Paris, UMR 1153 Centre of Research in Epidemiology and Statistics (CRESS), Epidemiology and Clinical Statistics for Tumor, Respiratory, and Resuscitation Assessments Team, Service de Pneumologie, Hôpital Saint Louis, Paris, France
^l Université de Paris, Innovative Therapies in Hemostasis, Inserm, Paris, France
^m Hematology Department, AP-HP Hôpital Cochin, Paris, France
ⁿ Biosurgical Research Lab (Carpentier Foundation), AP-HP Hôpital Européen Georges Pompidou, Paris, France
^o Équipe de Prévention du Risque Infectieux, AP-HP Hôpital Bichat, Paris, France
^p Université de Paris, Inserm, IAME, Paris, France

^∗Corresponding author: Benjamin Terrier, MD, PhD, Hôpital Cochin, 75679 Paris Cedex 14, France.Hôpital Cochin75679 Paris Cedex 14France

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Abstract

Background

Severe coronavirus disease 2019 (COVID-19) is characterized by impaired type I interferon activity and a state of hyperinflammation leading to acute respiratory distress syndrome. The complement system has recently emerged as a key player in triggering and maintaining the inflammatory state, but the role of this molecular cascade in severe COVID-19 is still poorly characterized.

Objective

We aimed at assessing the contribution of complement pathways at both the protein and transcriptomic levels.

Methods

To this end, we systematically assessed the RNA levels of 28 complement genes in the circulating whole blood of patients with COVID-19 and healthy controls, including genes of the alternative pathway, for which data remain scarce.

Results

We found differential expression of genes involved in the complement system, yet with various expression patterns: whereas patients displaying moderate disease had elevated expression of classical pathway genes, severe disease was associated with increased lectin and alternative pathway activation, which correlated with inflammation and coagulopathy markers. Additionally, properdin, a pivotal positive regulator of the alternative pathway, showed high RNA expression but was found at low protein concentrations in patients with a severe and critical disease, suggesting its deposition at the sites of complement activation. Notably, low properdin levels were significantly associated with the use of mechanical ventilation (area under the curve = 0.82; P = .002).

Conclusion

This study sheds light on the role of the alternative pathway in severe COVID-19 and provides additional rationale for the testing of drugs inhibiting the alternative pathway of the complement system.

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Key words : Complement system, alternative pathway, COVID-19, SARS-CoV-2, immunology, hemostasis

Abbreviations used : COVID-19, SARS-CoV-2

Plan

Introduction

Results and discussion

Supported by the Fonds IMMUNOV, for Innovation in Immunopathology; the Institut national de la santé et de la recherche médicale (Inserm); a government grant managed by the Agence national de la recherche as part of the Investment for the Future program (ANR-10-IAHU-01); and by grants from the Agence national de la recherche (ANR-flash COVID-19 “AIROCovid” and “CoVarImm”). We also acknowledge funding from the Institut Pasteur for COVID-19 Research and an Institut Imagine MD-PhD Fellowship Program award supported by the Fondation Bettencourt Schueller (to J.H.).

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 149 - N° 2

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Severe COVID-19 is associated with hyperactivation of the alternative complement pathway - 03/02/22

Abstract

Background

Objective

Methods

Results

Conclusion

Plan

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