1.3 guillaume dumenil
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Transcript of 1.3 guillaume dumenil
CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
1CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
Arterial wall colonization by bacteria: a critical stage before chaos
Guillaume Dumenil
Avenir team - INSERM U970
Paris center for cardiovascular research (PARCC)Hôpital Européen Georges Pompidou (HEGP)
CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
Septicemia: when bacteria reach the bloodstream…
Gram -
Gram +
FungiAspergillus
N. meningitidis
S. aureusS. pneumoniae
S. pyogenes
E. coli
Vascular dysfunction leak
CoagulationInflammation
Meningitis….
Sepsis in the US:800 000 deaths/year
… and colonize blood vessels
P. aeruginosa
C. albicans
CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
The Neisseria meningitidis model
2- Crossing of theepithelium
3- Proliferation in the blood
5- Proliferation in the cerebrospinal fluid
4- Crossing of the blood-brain barrier
Meningitis
Septicemia
Vessel damagePurpura fulminans
1- Colonization of the Nasopharynx
CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
Building relevant septicemia models: major challenges
• Blood flow generated mechanical forces
• Specific tissue architecture • Species specificity
Flow
rF
T
V D
• Microcirculation
10 µm
- ECM- Surrounding cells- Microenvironement
CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
Interaction with the endothelium is mediated by type IV pili
5
Agreggation
Fiber PilE
Adhesion
Type IV pili are involved in all stages of blood vessel colonization
Neisseria meningitidis
CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
Stage 1: site of adhesion determined by shear stress
Pump500µm
Bacteria are targeted to cerebral microcirculation
• Adhesion In vitro • Shear stress levels in vivoIntravital imaging
Mairey et al. J Exp Med 2006
CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
Stage 2: Intense cross-talk between cells and bacteria
7
In absence of plasma membrane
reorganization
Microcolony disruption
Live imaging
Biofilm-like structure
Bacteria
Cellular protrusions
Bacteria manipulate host cells to resist shear stress
Mikaty et al. PLOS Path. 2006
CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
Stage 3: Detachment is a highly regulated process
Chamot-Rooke Science 2011
Periplasm
Innermembraine Posttranslational
Modificationsof type IV pili
Major pilin
PptB Top down mass spectrometryPatent pending
The PptB enzyme is a possible therapeutic target
CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
Perspectives
• Each of these steps are potential targets (pathogen and host)
• From Neisseria meningitidis to other septicemia-causing pathogens?
• Need for new models to study these specific infections- In vitro models reproducing the specific geometry of
capillaries - In vivo models taking into account the human specificity
9
Vascular dysfunctionin septicemia
1 2 3