Complement factor D targeting protects endotheliopathy in organoid and monkey models of COVID-19.
CFD
SARS-CoV-2
acid-switch half-life extended antibody
complement
cynomolgus macaque
endotheliopathy
iPSC
thrombopathy
vascular organoid
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
05 10 2023
05 10 2023
Historique:
received:
01
11
2022
revised:
04
07
2023
accepted:
01
09
2023
pmc-release:
05
10
2024
medline:
9
10
2023
pubmed:
7
10
2023
entrez:
6
10
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37802037
pii: S1934-5909(23)00322-3
doi: 10.1016/j.stem.2023.09.001
pmc: PMC10575686
mid: NIHMS1930624
pii:
doi:
Substances chimiques
Complement Factor D
EC 3.4.21.46
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1315-1330.e10Subventions
Organisme : NIDDK NIH HHS
ID : DP2 DK128799
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK078392
Pays : United States
Informations de copyright
Copyright © 2023 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests N.S. and T.T. are patent holders associated with the technology described in this project.
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