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.

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) .