Breaking the wall: Targeting of the endothelium by pathogenic bacteria

INSERM, U895, Toxines Microbiennes dans la Relation Hôte Pathogènes, Centre Méditerranéen de Médecine Moléculaire, C3M, Nice, 06204, Cedex 3, France.
Nature Reviews Microbiology (Impact Factor: 23.57). 02/2010; 8(2):93-104. DOI: 10.1038/nrmicro2269
Source: PubMed


The endothelium lining blood and lymphatic vessels is a key barrier separating body fluids from host tissues and is a major target of pathogenic bacteria. Endothelial cells are actively involved in host responses to infectious agents, producing inflammatory cytokines, controlling coagulation cascades and regulating leukocyte trafficking. In this Review, a range of bacteria and bacterial toxins are used to illustrate how pathogens establish intimate interactions with endothelial cells, triggering inflammatory responses and coagulation processes and modifying endothelial cell plasma membranes and junctions to adhere to their surfaces and then invade, cross and even disrupt the endothelial barrier.

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Available from: Marc Lecuit,
    • "Numerous pathogens disrupt the endothelial barrier function of the host via targeting the organization of the actin cytoskeleton [Lemichez et al., 2010; Aktories et al., 2011]. For example, vascular leakage, edema, and hemorrhages are hallmarks of toxemia during systemic infection by the Gram-positive bacterium Bacillus anthracis [Abramova et al., 1993; Cui et al., 2004; Moayeri and Leppla, 2009]. "
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    ABSTRACT: It remains a challenge to decode the molecular basis of the long-term actin cytoskeleton rearrangements that are governed by the reprogramming of gene expression. Bacillus anthracis lethal toxin (LT) inhibits mitogen-activated protein kinase (MAPK) signaling, thereby modulating gene expression, with major consequences for actin cytoskeleton organization and the loss of endothelial barrier function. Using a laser ablation approach, we characterized the contractile and tensile mechanical properties of LT-induced stress fibers. These actin cables resist pulling forces that are transmitted at cell-matrix interfaces and at cell-cell discontinuous adherens junctions. We report that treating the cells with trichostatin A (TSA), a broad range inhibitor of histone deacetylases (HDACs), or with MS-275, which targets HDAC1, 2 and 3, induces stress fibers. LT decreased the cellular levels of HDAC1, 2 and 3 and reduced the global HDAC activity in the nucleus. Both the LT and TSA treatments induced Rnd3 expression, which is required for the LT-mediated induction of actin stress fibers. Furthermore, we reveal that treating the LT-intoxicated cells with garcinol, an inhibitor of histone acetyl-transferases (HATs), disrupts the stress fibers and limits the monolayer barrier dysfunctions. These data demonstrate the importance of modulating the flux of histone acetylation in order to control actin cytoskeleton organization and the endothelial cell monolayer barrier. This article is protected by copyright. All rights reserved.
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    • "As such, the endothelium represents a significant barrier for parasite entry into target tissues. Penetration of the endothelial barrier by pathogens is an emerging field, and various pathogens contend with the barrier using different strategies [31], [32]. We speculated that there were at least three active mechanisms by which T. cruzi could escape the blood stream. "
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    PLoS ONE 12/2013; 8(12):e81187. DOI:10.1371/journal.pone.0081187 · 3.23 Impact Factor
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    • "The endothelial tight junction membrane proteins occludin and claudins [12,34,49] are also susceptible to endoproteolysis within their extracellular domains, particularly by metalloproteinases [47,52,53]. SDS-PAGE/IB analysis similar as that performed for VE-cadherin revealed an early and complete disappearance of intact occludin (Mr ≈ 63 kDa) from EC cultures exposed to 10% PAO1-Sec for a period as short as 1 h, or to 1 to 5% secretome for 24 h, that was accompanied by the occurrence of cell-associated fragments with Mr in the range of ≈ 47 to 57 kDa (Figure 7A). "
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