1.3 guillaume dumenil

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  • 1- Certain pathogens reach the bloodstream during the infection process, this is generally a sign of high severity of the disease 2- Pathogens are diverse 3- Lead to a limited number of effects that have to do with the specific functions of blood vessels
  • Species specificity eg adhesion
  • Fin: we have shown that
  • Detachment > 2 consequences
  • 1.3 guillaume dumenil

    1. 1. 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
    2. 2. Septicemia: when bacteria reach the bloodstream… Gram - Gram + Fungi Aspergillus N. meningitidis S. aureus S. pneumoniae S. pyogenes E. coli Vascular dysfunction leak Coagulation Inflammation Meningitis … . Sepsis in the US: 800 000 deaths/year … and colonize blood vessels P. aeruginosa C. albicans
    3. 3. The Neisseria meningitidis model 2- Crossing of the epithelium 3- Proliferation in the blood 5- Proliferation in the cerebrospinal fluid 4- Crossing of the blood-brain barrier Meningitis Septicemia Vessel damage Purpura fulminans 1- Colonization of the Nasopharynx
    4. 4. Building relevant septicemia models: major challenges • Blood flow generated mechanical forces • Specific tissue architecture • Species specificity • Microcirculation 10 µm - ECM - Surrounding cells - Microenvironement Flow r F T V D
    5. 5. Interaction with the endothelium is mediated by type IV pili Agreggation Fiber PilE Adhesion Type IV pili are involved in all stages of blood vessel colonization Neisseria meningitidis
    6. 6. Stage 1: site of adhesion determined by shear stress Pump 500µm Bacteria are targeted to cerebral microcirculation •  Adhesion In vitro • Shear stress levels in vivo Intravital imaging Mairey et al. J Exp Med 2006
    7. 7. Stage 2: Intense cross-talk between cells and bacteria 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
    8. 8. Stage 3: Detachment is a highly regulated process Chamot-Rooke Science 2011 Periplasm Inner membraine Posttranslational Modifications of type IV pili Major pilin PptB Top down mass spectrometry Patent pending The PptB enzyme is a possible therapeutic target
    9. 9. Perspectives <ul><li>Each of these steps are potential targets (pathogen and host) </li></ul><ul><li>From Neisseria meningitidis to other septicemia-causing pathogens? </li></ul><ul><li>Need for new models to study these specific infections </li></ul><ul><li>- In vitro models reproducing the specific geometry of capillaries - In vivo models taking into account the human specificity </li></ul>Vascular dysfunction in septicemia 1 2 3
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