Association of COVID-19 inflammation with activation of the C5a–C5aR1 axis

Authors: Julien Carvelli 1 2, Olivier Demaria 3, Frédéric Vély 4 5, Luciana Batista 3, Nassima Chouaki Benmansour 6 7, Joanna Fares 3, Sabrina Carpentier 3, Marie-Laure Thibult 3, Ariane Morel 3, Romain Remark 3, Pascale André 3, Agnès Represa 3, Christelle Piperoglou 4 5, Explore COVID-19 IPH group; Pierre Yves Cordier 6, Erwan Le Dault 6, Christophe Guervilly 2 8, Pierre Simeone 2 9, Marc Gainnier 1 2, Yannis Morel 3, Mikael Ebbo 4 10, Nicolas Schleinitz 4 10, Eric Vivier 11 12 13, Explore COVID-19 Marseille Immunopole group

Online: https://www.nature.com/articles/s41586-020-2600-6

Issue: Nature. 2020 Jul 29. doi: 10.1038/s41586-020-2600-6.

Abstract

Coronavirus disease 2019 (COVID-19) is a new pandemic disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)¹. The C5a anaphylatoxin and its receptor C5aR1 (CD88) play a key role in the initiation and maintenance of several inflammatory responses, by recruiting and activating neutrophils and monocytes in the lungs¹. We provide a longitudinal analysis of immune responses, including immune cell phenotyping and assessments of the soluble factors present in the blood and broncho-alveolar lavage fluid (BALF) of patients at various stages of COVID-19 severity: paucisymptomatic, pneumonia and acute respiratory distress syndrome (ARDS). We report an increase in soluble C5a levels proportional to COVID-19 severity and high levels of C5aR1 expression in blood and pulmonary myeloid cells, supporting a role for the C5a-C5aR1 axis in the pathophysiology of ARDS. Anti-C5aR1 therapeutic monoclonal antibodies (mAbs) prevented C5a-mediated human myeloid cell recruitment and activation, and inhibited acute lung injury (ALI) in human C5aR1 knockin mice. These results suggest that C5a-C5aR1 axis blockade might be used as a means of limiting myeloid cell infiltration in damaged organs and preventing the excessive lung inflammation and endothelialitis associated with ARDS in COVID-19 patients.

AUTHOR AFFILIATIONS

1. Assistance Publique des Hôpitaux de Marseille, Hôpital de la Timone, Réanimation des Urgences, Marseille, France.
2. Aix Marseille Univ, Marseille, France.
3. Innate Pharma, Marseille, France.
4. Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.
5. Assistance Publique des Hôpitaux de Marseille, Hôpital de la Timone, Immunology, Marseille Immunopole, Marseille, France.
6. Hôpital d’Instruction des Armées Laveran, Marseille, France.
7. Assistance Publique des Hôpitaux de Marseille, Marseille, France.
8. Assistance Publique des Hôpitaux de Marseille, Hôpital Nord, Réanimation des Détresses Respiratoires et Infections Sévères, Aix-arseille Université, Marseille, France.
9. Assistance Publique des Hôpitaux de Marseille, Hôpital de la Timone, Réanimation Polyvalente, Aix-Marseille Université, Marseille, France.
10. Assistance Publique des Hôpitaux de Marseille, Hôpital de la Timone, Internal Medicine, Marseille, France.
11. Innate Pharma, Marseille, France.
12. Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.
13. Assistance Publique des Hôpitaux de Marseille, Hôpital de la Timone, Immunology, Marseille Immunopole, Marseille, France.