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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.

Purpura fulminans (PF) is a dreadful and frequent complication of Neisseria meningitidis invasive infection, and is associated with a high mortality rate. This syndrome begins with dermal microvessels thrombosis that rapidly lead to hemorrhagic skin necrosis. In this review, we discuss the prothrombotic events occurring during meningococcal infection. Moreover, recent data from an experimental mouse model have highlighted the critical role of the meningococcus adhesion to the endothelium in the development of PF lesions, thus opening new therapeutic perspectives., (© FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Neisseria meningitidis is a strict human pathogen that closely interacts with human endothelial cells via type IV pili in vitro. To decipher whether this interaction plays a role in vivo, we set up an experimental model of fulminant meningococcemia in human skin grafted SCID mice using the wild-type strain 2C4.3. Human skin and mouse tissues were sampled 24 hours after bacterial challenge for histopathology, immunohistochemistry and ultrastructural analysis. In all infected mice, N. meningitidis targeted the human vasculature, leading to bacterial and blood thrombi, infectious vasculitis and vascular leakage. Mouse vessels, including brain vessels, remained unaffected by the infectious and thrombotic process, and a nonpiliated Δ pilE derivative of 2C4.3 failed to target human graft vessels and to induce vascular damages. These data demonstrate that N. meningitidis targets human endothelial cells in vivo and that this interaction triggers the vascular damages that characterize purpura fulminans.

Neisseria meningitidisis the causative agent of cerebrospinal meningitis and that of a rapidly progressing fatal septic shock known aspurpura fulminans. Meningococcemia is characterized by bacterial adhesion to human endothelial cells of the microvessels. Host specificity has hampered studies on the role of blood vessels colonization inN. meningitidisassociated pathogenesis. In this work, using a humanized model of SCID mice allowing the study of bacterial adhesion to human cells in anin vivocontext we demonstrate that meningococcal colonization of human blood vessels is a prerequisite to the establishment of sepsis and lethality. To identify the molecular pathways involved in bacterial virulence, we performed transposon insertion site sequencing (Tn-seq)in vivo. Our results demonstrate that 36% of the genes that are important for growth in the blood of mice are dispensable when bacteria colonize human blood vessels, suggesting that human endothelial cells lining the blood vessels are feeding niches forN. meningitidis in vivo. Altogether, our work proposes a new paradigm for meningococcal virulence in which colonization of blood vessels is associated with metabolic adaptation and sustained bacteremia responsible for sepsis and subsequent lethality. [ABSTRACT FROM AUTHOR]

Neisseria meningitidis is an extracellular pathogen, which, once in the bloodstream, has the ability to form microcolonies on the apical surface of endothelia. Pathogen interaction with microvessels is mediated by bacterial type IV pili and two receptors on endothelial cells: CD147 and the β2-adrenoceptor. CD147 facilitates the adhesion of diplococci to the endothelium, whereas the β2-adrenoceptor facilitates cell signaling, and crossing of the blood–brain barrier. In this review, we discuss how meningococcal interaction with endothelial cells is responsible for the specific clinical features of invasive meningococcal infection such as meningitis, and a peripheral thrombotic/vascular leakage syndrome possibly leading to purpura fulminans. [ABSTRACT FROM AUTHOR]