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

Abstract

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.

• Authors: Eri Kawakami, Norikazu Saiki, Yosuke Yoneyama, Chiharu Moriya, Mari Maezawa, Shuntaro Kawamura, Akiko Kinebuchi, Tamaki Kono, Masaaki Funata, Ayaka Sakoda, Shigeru Kondo, Takeshi Ebihara, Hisatake Matsumoto, Yuki Togami, Hiroshi Ogura, Fuminori Sugihara, Daisuke Okuzaki, Takashi Kojima, Sayaka Deguchi, Sebastien Vallee, Susan McQuade, Rizwana Islam, Madhusudan Natarajan, Hirohito Ishigaki, Misako Nakayama, Cong Thanh Nguyen, Yoshinori Kitagawa, Yunheng Wu, Kensaku Mori, Takayuki Hishiki, Tomohiko Takasaki, Yasushi Itoh, Kazuo Takayama, Yasunori Nio, Takanori Takebe
• Journal: Cell stem cell (Cell Stem Cell) Vol. 30 Issue 10 Pg. 1315-1330.e10 (10 05 2023) ISSN: 1875-9777 [Electronic] United States
• PMID: 37802037 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• Complement Factor D

Topics

• Animals
• Humans
• COVID-19
• SARS-CoV-2
• Complement Factor D
• Endothelial Cells
• Haplorhini