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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)

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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

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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

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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

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Interaction with the endothelium is mediated by type IV pili

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Agreggation

Fiber PilE

Adhesion

Type IV pili are involved in all stages of blood vessel colonization

Neisseria meningitidis

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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

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Stage 2: Intense cross-talk between cells and bacteria

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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

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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

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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

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Vascular dysfunctionin septicemia

1 2 3

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