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

ABSTRACT 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, Sep 28, 2015
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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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    ABSTRACT: Chagas heart disease, the leading cause of heart failure in Latin America, results from infection with the parasite Trypanosoma cruzi. Although T. cruzi disseminates intravascularly, how the parasite contends with the endothelial barrier to escape the bloodstream and infect tissues has not been described. Understanding the interaction between T. cruzi and the vascular endothelium, likely a key step in parasite dissemination, could inform future therapies to interrupt disease pathogenesis. We adapted systems useful in the study of leukocyte transmigration to investigate both the occurrence of parasite transmigration and its determinants in vitro. Here we provide the first evidence that T. cruzi can rapidly migrate across endothelial cells by a mechanism that is distinct from productive infection and does not disrupt monolayer integrity or alter permeability. Our results show that this process is facilitated by a known modulator of cellular infection and vascular permeability, bradykinin, and can be augmented by the chemokine CCL2. These represent novel findings in our understanding of parasite dissemination, and may help identify new therapeutic strategies to limit the dissemination of the parasite.
    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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    ABSTRACT: Within the vasculature, uncontrolled pericellular proteolysis can lead to disruption of cell-to-cell and cell-to-matrix interactions and subsequent detachment-induced cell apoptosis, or anoikis, contributing to inflammatory vascular diseases, with the endothelium as the major target. Most studies so far have focused on endogenous proteinases. However, during bloodstream infections, bacterial proteinases may also trigger endothelial anoikis. We thus investigated the potential apoptotic activity of the proteinases secreted by the haematotropic opportunistic pathogen, Pseudomonas aeruginosa, and particularly its predominant metalloproteinase, LasB. For this, we used the secretome of the LasB-expressing pseudomonal strain, PAO1, and compared it with that from the isogenic, LasB-deficient strain (PAO1∆lasB), as well as with purified LasB. Secretomes were tested for apoptotic activity on cultured human endothelial cells derived from the umbilical vein or from the cerebral microvasculature. We found that the PAO1 secretome readily induced endothelial cell anoikis, as did secretomes of LasB-positive clinical pseudomonal isolates, while the PAO1∆lasB secretome had only a limited impact on endothelial adherence and viability. Notably, purified LasB reproduced most of the effects of the LasB-containing secretomes, and these were drastically reduced in the presence of the LasB-selective inhibitor, phosphoramidon. A precocious and extensive LasB-dependent degradation of several proteins associated with the endothelial extracellular matrix, fibronectin and von Willebrand factor, was observed by immunofluorescence and/or immunoblotting analysis of cell cultures. Moreover, the PAO1 secretome, but not that from PAO1∆lasB, specifically induced rapid endoproteolysis of two major interendothelial junction components, VE-cadherin and occludin, as well as of the anti-anoikis, integrin-associated urokinase receptor, uPAR. Taken as a prototype for exogenous haemorrhagic proteinases, pseudomonal LasB thus appears to induce endothelial anoikis not only via matrilysis, as observed for many pro-apoptotic proteinases, but also via cleavage of some essential cell-to-cell and cell-to-matrix adhesion receptors implicated in the maintenance of the endothelial barrier.
    PLoS ONE 09/2013; 8(9):e75708. DOI:10.1371/journal.pone.0075708 · 3.23 Impact Factor
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    • "In this migration process, the parasite must interact with laminin, fibronectin, collagen, heparin and heparan sulfate and hydrolyze some of them [52]. As the major component, collagen forms the ECM scaffold and constitutes an important natural barrier against infections by pathogens [53]. "
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    ABSTRACT: The trypanosomatids Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp. cause Chagas disease, leishmaniasis and human African trypanosomiasis, respectively. It is estimated that over 10 million people worldwide suffer from these neglected diseases, posing enormous social and economic problems in endemic areas. There are no vaccines to prevent these infections and chemotherapies are not adequate. This picture indicates that new chemotherapeutic agents must be developed to treat these illnesses. For this purpose, understanding the biology of the pathogenic trypanosomatid-host cell interface is fundamental for molecular and functional characterization of virulence factors that may be used as targets for the development of inhibitors to be used for effective chemotherapy. In this context, it is well known that proteases have crucial functions for both metabolism and infectivity of pathogens and are thus potential drug targets. In this regard, prolyl oligopeptidase and oligopeptidase B, both members of the S9 serine protease family, have been shown to play important roles in the interactions of pathogenic protozoa with their mammalian hosts and may thus be considered targets for drug design. This review aims to discuss structural and functional properties of these intriguing enzymes and their potential as targets for the development of drugs against Chagas disease, leishmaniasis and African trypanosomiasis.
    Current Medicinal Chemistry 03/2013; 20(25). DOI:10.2174/09298673113209990121 · 3.85 Impact Factor
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