A complement atlas identifies interleukin-6–dependent alternative pathway dysregulation as a key druggable feature of COVID-19
Science Translational Medicine, 2023
Van Damme K., Hoste L., Declercq J., De Leeuw E., Maes B., Martens L., Colman R., Browaeys R., Bosteels C., Verwaerde S., Vermeulen N., Lameire S., Debeuf N., Deckers J., Stordeur P., Depuydt P., Van Braeckel E., Vandekerckhove L., Guilliams M., Schetters S., Haerynck F., Tavernier S., Lambrecht B.
Disease area | Application area | Sample type | Products |
---|---|---|---|
Infectious Diseases | Pathophysiology | Serum | Olink Explore 3072/384 |
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.