A complement atlas identifies interleukin-6–dependent alternative pathway dysregulation as a key druggable feature of COVID-19

Karel F.A. Van Damme*, Levi Hoste, Jozefien Declercq, Elisabeth De Leeuw, Bastiaan Maes, Liesbet Martens, Roos Colman, Robin Browaeys, Cédric Bosteels, Stijn Verwaerde, Nicky Vermeulen, Sahine Lameire, Nincy Debeuf, Julie Deckers, Patrick Stordeur, Pieter Depuydt, Eva Van Braeckel, Linos Vandekerckhove, Martin Guilliams, Sjoerd T.T. SchettersFilomeen Haerynck, Simon J. Tavernier, Bart N. Lambrecht*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Improvements in COVID-19 treatments, especially for the critically ill, require deeper understanding of the mechanisms driving disease pathology. The complement system is not only a crucial component of innate host defense but can also contribute to tissue injury. Although all complement pathways have been implicated in COVID-19 pathogenesis, the upstream drivers and downstream effects on tissue injury remain poorly defined. We demonstrate that complement activation is primarily mediated by the alternative pathway, and we provide a comprehensive atlas of the complement alterations around the time of respiratory deterioration. Proteomic and single-cell sequencing mapping across cell types and tissues reveals a division of labor between lung epithelial, stromal, and myeloid cells in complement production, in addition to liver-derived factors. We identify IL-6 and STAT1/3 signaling as an upstream driver of complement responses, linking complement dysregulation to approved COVID-19 therapies. Furthermore, an exploratory proteomic study indicates that inhibition of complement C5 decreases epithelial damage and markers of disease severity. Collectively, these results support complement dysregulation as a key druggable feature of COVID-19.

Original languageEnglish
Article numbereadi0252
JournalScience Translational Medicine
Volume15
Issue number710
DOIs
Publication statusPublished - 23 Aug 2023

Bibliographical note

Funding Information:
We owe gratitude to all patients and their families for participating in our trials and to all involved clinical teams. We thank the VIB Tech Watch Fund and the VIB Grand Challenges Program, which enabled the proteomic and biomarker analysis. Trial oversight and data collection were carried out at Ghent University Hospital by the clinical research coordinators at the Department of Respiratory Medicine (S. Vermeersch, B. Demeyere, A. Delporte, A. Vandecauter, and V. Parrein), the study nurses at the Intensive Care Unit (D. Vermeiren) and Center for Primary Immunodeficiency (K. Claes), the Health, Innovation and Research Institute (HIRUZ) (C. Van Der Straeten, C. Clauwaert, J. Tommelein, H. De Naeyer, D. Loncke, K. Hanife, L. Vanlanduyt, E. Doolaege, S. Vanderschaeghe, L. Borgers, and S. De Buyser), and biobank requirements were fulfilled by the colleagues of the Respiratory Infection and Defense laboratory and Lung Research Lab (A. Neesen, I. De Borle, and T. Maes) at Ghent University, for which we thank them. Clinical samples were processed by many fantastic colleagues (L. Sys, H. Aegerter, U. Smole, K. Deswarte, L. Naesens, H. Flipts, H. Hammad, V. Debacker, J. Van Moorleghem, L. Roels, N. Cabooter, Z. Declercq, and R. Schuppers). We thank the UCB team (C. Brittain, L. Detalle, J. Greenin, M. Lens, and M. Lalla) for the collaboration on the ZILUCOV trial. The Inflammation Research Center web team (A. Soete) and VIB Single Cell Core (K. Verstaen) helped launching the Complement Atlas web portal. Administrative and ethical advice was provided by G. Verhaegen and R. Custers. We thank H. Baggali and N. Gerebtsov for providing linguistic advice.This work was funded by the Vlaams Instituut voor Biotechnologie (VIB) Grand Challenges programs M901BALA-GCP-COVID-19-SARPAC TRIAL and M902BALA-GCP-COVID-19-IL6-IL1 TRIAL (to B.N.L.), the VIB Tech Watch Fund (to B.N.L.), the Chan Zuckerberg Initiative COVID atlas project 2020-216717 (to M.G.), the Ghent University COVID-Track project BOFCOV;01C04620 (to B.N.L.), the Fonds voor wetenschappelijk onderzoek (FWO) COVID grant G0G4520N (to L.V., M.G., and B.N.L.), and a Ghent University Methusalem grant 01 M01521 (to B.N.L.).

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