Professor Xavier Nassif @ MRF's Meningitis & Septicaemia in Children & Adults 2015
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1) Meningococcal sepsis is a disease caused by Neisseria meningitidis that can lead to multi-organ failure and extensive necrosis of the skin. It is characterized by thrombosis and vasculitis. 2) Experiments using a human skin transplantation model in mice showed that non-piliated N. meningitidis strains did not colonize the skin grafts or induce thrombosis or vascular damage. 3) Two endothelial cell membrane receptors, an "adhesion receptor" and a "signaling receptor", are required for N. meningitidis type IV pili to activate the protein C pathway in endothelial cells, which promotes thrombotic lesions in meningococcal sepsis.
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Professor Xavier Nassif @ MRF's Meningitis & Septicaemia in Children & Adults 2015
- 1. Meningococcemia, a disease of the endothelial cells Xavier Nassif Institut Necker-Enfants Malades Université Paris Descartes Paris, France
- 2. PHARYNX CSF BLOOD CARRIER Meningococcal sepsis Clinically : multiorgan failure, extensive necrotic purpura. . Histologically : thrombosis, vasculitis, hemorragic necrosis (adrenal, skin) MENINGITIS
- 3. Heart Kidney
- 4. Human skin transplantation model model in SCID mice 1 cm x 1 cm Before After CB17/SCID 6 week-old females Before After
- 5. Nm targets human endothelial cells (immuno histochemistry) Anti human CD31 Anti Nm
- 6. PilD PilF PilT E Assembly Retraction Outer membrane Inner membrane PilC PilQ PilW Assembly PilM, N, O, P Stabilization PilC, G, H, I, J, K, W Maturation PilC, I, J, K, W PilE! Minor pilins! (PilX, PilV, ComP)! Prepilin Minor pilins! assembly! re!traction! (PilT)! emergence !on the! (PilQ)! Functional Tfp (PilE, PilX, PilV, ComP)! (PilD, F, M, N, O, P)! (PilC, G, H, I, J, K, W)! cell surface! (Craig et al, Molecular Cell 2006)
- 7. Non piliated strains do not colonize human skin grafts and do not induce thrombosis nor vascular damage X 100 X 1000 100 µm 100 µm 100 µm 10 µm 10 µm 10 µm Nm antigen was only found within the cytoplasm of circulating or resident phagocytes
- 9. CD147 β2AR Adhesion PilE PilV PilE, PilV Signalling Type IV pilus Receptor : Cellular Complex involving an « Adhesion Receptor » and a « Signalling Receptor » Receptors for N. meningitidis Type IV pili Coureuil et al, Cell, 2010 Bernard et al, Nature Medicine, 2014
- 10. ICAM-1 ICAM-2 CD44 E-selectin Ezrin-Moesin Coureuil et al, Science, 2009 Cdc42 Par3/PKCζ/Par6 complex p120 β α Z0-1 Claudins VE-Cadherin permeability Bacterial diffusion Type IV pilus-mediated signaling events Doulet et al, J Cell Biol, 2006 Lambotin et al J Cell Science, 2005 Eugene et al, J Cell Science, 2002 Hofffmann et al, J Cell Biol, 2001
- 11. How this meningococcal endothelial cells interaction promotes the thrombotic leakage syndrome responsible for Purpura fulminans ?
- 12. Two endothelial membranous receptors are required for the activation of protein C Coagulation triggers (endotoxin, pro-inflammatory cytokines) Coagulation cascade Fibrinogen Fibrin (thrombus) Endothelial cells TM Thrombin Thr Thr PCaPC EPCR PC -‐
- 13. Heart Kidney
- 14. Jean-Philippe Barnier Jean Bergougnioux Emmanuelle Bille Terry Brissac Elena Capel Malo Mathieu Coureuil Daniel Euphrasie Eric Frapy Gaël Gesbert Anne Jamet Olivier Join-Lambert Hervé Lécuyer Julie Meyer Zoé Virion Institut Cochin - Paris Team 11 – INSERM U1151 – INEM - Paris Alain Schmitt (Electron Microscopy) Sandrine Bourdoulous Stefano Marullo