Association of COVID-19 inflammation with activation of the C5a–C5aR1 axis
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Abstract
Coronavirus disease 2019 (COVID-19) is a disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic 1. The C5a complement factor and its receptor C5aR1 (also known as CD88) have a key role in the initiation and maintenance of several inflammatory responses by recruiting and activating neutrophils and monocytes 1. Here we provide a longitudinal analysis of immune responses, including phenotypic analyses of immune cells and assessments of the soluble factors that are present in the blood and bronchoalveolar lavage fluid of patients at various stages of COVID-19 severity, including those who were paucisymptomatic or had pneumonia or acute respiratory distress syndrome. The levels of soluble C5a were increased in proportion to the severity of COVID-19 and high expression levels of C5aR1 receptors were found in blood and pulmonary myeloid cells, which supports a role for the C5a-C5aR1 axis in the pathophysiology of acute respiratory distress syndrome. Anti-C5aR1 therapeutic monoclonal antibodies prevented the C5a-mediated recruitment and activation of human myeloid cells, and inhibited acute lung injury in human C5aR1 knock-in mice. These results suggest that blockade of the C5a-C5aR1 axis could be used to limit the infiltration of myeloid cells in damaged organs and prevent the excessive lung inflammation and endothelialitis that are associated with acute respiratory distress syndrome in patients with COVID-19.
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SARS-CoV-2 infection strongly activates complement and other innate immune pathways such as TLR4 and the inflammasome, leading to increased IL-1β and IL-18 levels.
“SARS-CoV-2 infection has been documented to strongly activate complement and to activate other innate immune pathways such as TLR4 and the inflammasome, which leads to increased IL-1 β and IL-18 levels. 137-142”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [137]
The supplied Abstract passages report elevated C5a and other evidence of complement activation in COVID-19 patients. They also report IL-1β in lung fluid from patients with ARDS, but do not establish that TLR4 or inflammasome activation caused it, or report the claimed increase in IL-18. The paper discusses TLR7/TLR8 stimulation instead; no page numbers are available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOther key innate cytokines elevated during COVID-19 include TNFα and IL-6, which is increased by IL-1β.
“Other key innate cytokines that are elevated during COVID-19 include TNF α and IL-6, which is increased by IL-1 β . 137-142”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [137]
The passage discussing Fig. 1a reports increased plasma IL-6 with COVID-19 severity, and the passage discussing Fig. 3a–d detects TNF-α and IL-6 in lung lavage fluid and reports higher expression of their genes in pulmonary myeloid cells. The paper does not say that IL-1β increases IL-6; its monocyte experiment instead reports increased IL-6 production with C5a stimulation. (LLM, conf=0.88)
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- Authors
- Carvelli, J., Demaria, O., Vély, F., Batista, L., Chouaki Benmansour, N., Fares, J., Carpentier, S., Thibult, M.-L., Morel, A., Remark, R., André, P., Represa, A., Piperoglou, C., the Explore COVID-19 IPH group, Assante Miranda, L., Baron, W., Belaid, N., Caillet, C., Caraguel, F., Carrette, B., Carrette, F., Chanuc, F., Courtois, R., Fenis, A., Giordano, M., Girard-Madoux, M., Giraudon-Paoli, M., Gourdin, N., Grondin, G., Guillot, F., Habif, G., Jaubert, S., Lopez, J., Le Van, M., Lovera, N., Mansuy, M., Bonnet, E., Sansaloni, A., Reboul, A., Mitry, E., Nekkar-Constant, C., Péri, V., Ricaut, P., Simon, L., Vallier, J.-B., Vétizou, M., Zerbib, R., the Explore COVID-19 Marseille Immunopole group, Ugolini, S., Etiennot, M., Galluso, J., Lyonnet, L., Forel, J.-M., Papazian, L., Velly, L., André, B., Briantais, A., Faucher, B., Jean, E., Seguier, J., Veit, V., Harlé, J.-R., Pastorino, B., Delteil, C., Daniel, L., Boudsocq, J.-P., Clerc, A., Delmond, E., Vidal, P.-O., Savini, H., Coutard, B., Cordier, P. Y., Le Dault, E., Guervilly, C., Simeone, P., Gainnier, M., Morel, Y., Ebbo, M., Schleinitz, N., & Vivier, E.
- Affiliations
- Aix-Marseille Université (FR)
- Innate Pharma (France) (FR)
- Centre National de la Recherche Scientifique (FR)
- Assistance Publique Hôpitaux de Marseille (FR)
- Hôpital Laveran (FR)
- Inserm (FR)
- ORCID
- Carvelli, Julien
- Demaria, Olivier
- Fares, Joanna
- Carpentier, Sabrina
- Morel, Ariane
- Courtois, Rachel
- Girard-Madoux, Mathilde
- Habif, Guillaume
- Mitry, Emmanuel
- Vallier, Jean-Baptiste
- Vétizou, Marie
- Ugolini, Sophie
- Forel, Jean-Marie
- Papazian, Laurent
- Velly, Lionel
- André, Baptiste
- Briantais, Antoine
- Seguier, Julie
- Harlé, Jean-Robert
- Pastorino, Boris
- Delteil, Clémence
- Daniel, Laurent
- Vidal, Pierre-Olivier
- Coutard, Bruno
- Cordier, Pierre Yves
- Guervilly, Christophe
- Simeone, Pierre
- Gainnier, Marc
- Schleinitz, Nicolas
- Vivier, Eric
- Venue
- Nature
- Published
- 2020-07-29
- Volume
- 588
- Issue
- 7836
- Pages
- 146-150
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7116884
- OpenAlex
- W3045715678
- Cited by
- 526
- References
- 39
- Citations by year
- 2026: 28 · 2025: 48 · 2024: 63 · 2023: 84 · 2022: 109 · 2021: 153 · 2020: 40 · 2019: 1
- FWCI
- 12.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Aix-Marseille Université
- European Commission (HORIZON2020)
- Agence Nationale de la Recherche (ANR-17-RHUS-0007, ANR-17)
- Institut National de la Santé et de la Recherche Médicale
- Centre National de la Recherche Scientifique
- H2020 European Research Council (875102, 694502)
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- COVID-19 pandemic, SARS-CoV-2, complement system, C5a receptor, acute respiratory distress syndrome, lung inflammation, myeloid cell recruitment, neutrophils, monocytes, acute lung injury, endothelial inflammation, bronchoalveolar lavage fluid, disease severity
- MeSH terms
- Cytokine Release Syndrome, COVID-19, SARS-CoV-2, Animals, Bronchoalveolar Lavage Fluid, Disease Models, Animal, Female, Humans, Inflammation, Lung, Mice, Inbred C57BL, Respiratory Distress Syndrome, Complement C5a, Myeloid Cells, CD11b Antigen, Receptor, Anaphylatoxin C5a, Mice, Acute Lung Injury
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