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An ADAM-10 dependent EPCR shedding links meningococcal interaction with endothelial cells to purpura fulminans.
- Source :
-
PLoS pathogens [PLoS Pathog] 2018 Apr 09; Vol. 14 (4), pp. e1006981. Date of Electronic Publication: 2018 Apr 09 (Print Publication: 2018). - Publication Year :
- 2018
-
Abstract
- Purpura fulminans is a deadly complication of Neisseria meningitidis infections due to extensive thrombosis of microvessels. Although a Disseminated Intra-vascular Coagulation syndrome (DIC) is frequently observed during Gram negative sepsis, it is rarely associated with extensive thrombosis like those observed during meningococcemia, suggesting that the meningococcus induces a specific dysregulation of coagulation. Another specific feature of N. meningitidis pathogenesis is its ability to colonize microvessels endothelial cells via type IV pili. Importantly, endothelial cells are key in controlling the coagulation cascade through the activation of the potent anticoagulant Protein C (PC) thanks to two endothelial cell receptors among which the Endothelial Protein C Receptor (EPCR). Considering that congenital or acquired deficiencies of PC are associated with purpura fulminans, we hypothesized that a defect in the activation of PC following meningococcal adhesion to microvessels is responsible for the thrombotic events observed during meningococcemia. Here we showed that the adhesion of N. meningitidis on endothelial cells results in a rapid and intense decrease of EPCR expression by inducing its cleavage in a process know as shedding. Using siRNA experiments and CRISPR/Cas9 genome edition we identified ADAM10 (A Disintegrin And Metalloproteinase-10) as the protease responsible for this shedding. Surprisingly, ADAM17, the only EPCR sheddase described so far, was not involved in this process. Finally, we showed that this ADAM10-mediated shedding of EPCR induced by the meningococcal interaction with endothelial cells was responsible for an impaired activation of Protein C. This work unveils for the first time a direct link between meningococcal adhesion to endothelial cells and a severe dysregulation of coagulation, and potentially identifies new therapeutic targets for meningococcal purpura fulminans.
- Subjects :
- ADAM10 Protein genetics
Amyloid Precursor Protein Secretases genetics
Bacterial Adhesion
Blood Coagulation physiology
Cells, Cultured
Endothelial Protein C Receptor genetics
Endothelium, Vascular metabolism
Endothelium, Vascular microbiology
Humans
Membrane Proteins genetics
Meningococcal Infections microbiology
Microvessels metabolism
Microvessels microbiology
Neisseria meningitidis physiology
Protein C genetics
Purpura Fulminans metabolism
Purpura Fulminans pathology
ADAM10 Protein metabolism
Amyloid Precursor Protein Secretases metabolism
Endothelial Protein C Receptor metabolism
Endothelium, Vascular pathology
Membrane Proteins metabolism
Meningococcal Infections complications
Microvessels pathology
Protein C metabolism
Purpura Fulminans etiology
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 14
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 29630665
- Full Text :
- https://doi.org/10.1371/journal.ppat.1006981