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. Schetters; Filomeen Haerynck; Simon J. Tavernier; Bart N. Lambrecht

doi:10.5281/zenodo.8192092

Published July 28, 2023 | Version 1

Dataset Open

A Complement Atlas identifies interleukin 6 dependent alternative pathway dysregulation as a key druggable feature of COVID-19.

1. Ghent University
2. Université Libre de Bruxelles

Improvements in COVID-19 treatments, especially for the critically ill, require deeper understanding of the mechanisms driving disease pathology. The complement system is 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.

Notes

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 BNL), the VIB Tech Watch Fund (to BNL), the Chan Zuckerberg Initiative COVID atlas project 2020-216717 (to MG), the Ghent University COVID-Track project BOFCOV;01C04620 (to BNL), the Fonds voor wetenschappelijk onderzoek (FWO) COVID grant G0G4520N (to LV, MG, and BNL) and a Ghent University Methusalem grant 01M01521 (to BNL) .

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complement.csv

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complement.csv md5:44ba6ec1d612ae1c526a8bfcab2a7eea	34.1 kB	Preview Download
complement_anti_C5.csv md5:634a57852469435f20b38759b655105d	13.9 kB	Preview Download
complement_function.csv md5:2d8e46717773c408ef46611680b4604e	1.2 MB	Preview Download
olink.csv md5:bc73102b08754c9bf1b0da4b0f9ef118	2.0 MB	Preview Download
README.txt md5:3256df5828c422c2ea83bbbe6097d1db	3.8 kB	Preview Download

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A Complement Atlas identifies interleukin 6 dependent alternative pathway dysregulation as a key druggable feature of COVID-19.

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complement.csv

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