A Complement Atlas identifies interleukin 6 dependent alternative pathway dysregulation as a key druggable feature of COVID-19.
DOI10.5281/zenodo.8192092Zenodo8192092MaRDI QIDQ6692513FDOQ6692513
Dataset published at Zenodo repository.
Roos Colman, Simon J Tavernier, Robin Browaeys, Cédric Bosteels, Eva van Braeckel, Liesbet Martens, Elisabeth de Leeuw, Sjoerd T.t. Schetters, Bart Lambrecht, Levi Hoste, Jozefien Declercq, Karel F.a. van Damme, Martin Guilliams, Nincy Debeuf, Sahine Lameire, Julie Deckers, Bastiaan Maes, Filomeen Haerynck, Pieter Depuydt, Linos Vandekerckhove, Patrick Stordeur, Stijn Verwaerde, Nicky Vermeulen
Publication date: 28 July 2023
Copyright license: Creative Commons Attribution 4.0 International
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.
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