professor xavier nassif @ mrf's meningitis & septicaemia in children & adults 2015
TRANSCRIPT
Meningococcemia, a disease of the ���endothelial cells
Xavier Nassif Institut Necker-Enfants Malades
Université Paris Descartes Paris, France
PHARYNX
CSF
BLOOD
CARRIER
Meningococcal sepsis
Clinically : multiorgan failure, extensive necrotic purpura.
. Histologically : thrombosis, vasculitis,
hemorragic necrosis (adrenal, skin)
MENINGITIS
Heart
Kidney
Human skin transplantation model model in SCID mice
1 cm x 1 cm Before After
CB17/SCID 6 week-old females
Before After
Nm targets human endothelial cells ���(immuno histochemistry)
Anti human CD31 Anti Nm
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)
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
Vasculitis
Thrombus
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
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
How this meningococcal endothelial cells interaction promotes the thrombotic leakage syndrome responsible for Purpura fulminans ?
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
PC aPC
EPCR
PC
-‐
Heart
Kidney
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