professor xavier nassif @ mrf's meningitis & septicaemia in children & adults 2015

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