An ADAM-10 dependent EPCR shedding links meningococcal interaction with endothelial cells to purpura fulminans

PLoS Pathog. 2018 Apr 9;14(4):e1006981. doi: 10.1371/journal.ppat.1006981. eCollection 2018 Apr.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM10 Protein / genetics
  • ADAM10 Protein / metabolism*
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Bacterial Adhesion
  • Blood Coagulation / physiology
  • Cells, Cultured
  • Endothelial Protein C Receptor / genetics
  • Endothelial Protein C Receptor / metabolism*
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / microbiology
  • Endothelium, Vascular / pathology*
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Meningococcal Infections / complications*
  • Meningococcal Infections / microbiology
  • Microvessels / metabolism
  • Microvessels / microbiology
  • Microvessels / pathology*
  • Neisseria meningitidis / physiology
  • Protein C / genetics
  • Protein C / metabolism*
  • Purpura Fulminans / etiology*
  • Purpura Fulminans / metabolism
  • Purpura Fulminans / pathology


  • Endothelial Protein C Receptor
  • Membrane Proteins
  • PROCR protein, human
  • Protein C
  • Amyloid Precursor Protein Secretases
  • ADAM10 Protein
  • ADAM10 protein, human

Grant support

This work was supported by an Agence Nationale de la Recherche grant (ANR-14-IFEC-0006-01 call ERANET INFECT-ERA 2014 – grant recipient SB), the grant program EMERGENCE from La Mairie de Paris (grant recipient MC) and a grant from the Meningitis Research Foundation (MRF 1602 – grant recipient XN). The laboratory of XN is supported by INSERM, CNRS, Université Paris Descartes, and the Fondation pour la Recherche Médicale (FRM DEQ20140329533). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.