Complement factor D targeting protects endotheliopathy in organoid and monkey models of COVID-19, 2023, Kawakami et al

Complement factor D targeting protects endotheliopathy in organoid and monkey models of COVID-19


Highlights

• Longitudinal proteomics reveals aberrant complement patterns in severe COVID-19
• Human PSC-vascular organoid models endotheliopathy by SARS-CoV-2 infection
• SARS-CoV-2 spike-ECD triggers inflammathrombosis in engineered human vessels
• Complement factor D antibody reduces inflammathrombosis in the primate COVID-19 model

Summary
COVID-19 is linked to endotheliopathy and coagulopathy, which can result in multi-organ failure. The mechanisms causing endothelial damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain elusive. Here, we developed an infection-competent human vascular organoid from pluripotent stem cells for modeling endotheliopathy.

Longitudinal serum proteome analysis identified aberrant complement signature in critically ill patients driven by the amplification cycle regulated by complement factor B and D (CFD). This deviant complement pattern initiates endothelial damage, neutrophil activation, and thrombosis specific to organoid-derived human blood vessels, as verified through intravital imaging. We examined a new long-acting, pH-sensitive (acid-switched) antibody targeting CFD. In both human and macaque COVID-19 models, this long-acting anti-CFD monoclonal antibody mitigated abnormal complement activation, protected endothelial cells, and curtailed the innate immune response post-viral exposure.

Collectively, our findings suggest that the complement alternative pathway exacerbates endothelial injury and inflammation. This underscores the potential of CFD-targeted therapeutics against severe viral-induced inflammathrombotic outcomes.

Graphical abstract


https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00322-3