Breaking the wall: Targeting of the endothelium by pathogenic bacteria

Article (PDF Available)inNature Reviews Microbiology 8(2):93-104 · February 2010with58 Reads
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.


    • "The endothelial cell (EC) monolayer of the vascular wall is a major target for pathogenic bacteria to systemically disseminate (Lemichez et al., 2010). ECs are highly mechanosensitive and respond to varying mechanical cues, including the stiffness of their extracellular matrix (ECM), by altering both their gene expression profiles and the organization of their cytoskeletons and adhesion architecture. "
    [Show abstract] [Hide abstract] ABSTRACT: 3 A Highly Quantitative Multi-Well Format Assay for Studying the Effect of Extracellular Matrix Mechanics on the Bacterial Infection of Endothelial Cells Effie Bastounis Julie A. Theriot Abstract Bacterial pathogens can cause systemic infections by disseminating from the initial focus of infection to distant organs through the blood vasculature. To colonize tissues from the bloodstream, many bacteria need to adhere to endothelial cells (ECs) that line the vessels’ inner lumen, invade them and then spread from cell to cell. ECs are highly mechanosensitive and respond to mechanical cues, including the stiffness of the matrix on which they adhere, by dynamically re-arranging their cytoskeleton, cell-cell adhesions, and adhesions to the extracellular matrix. We hypothesize that bacterial infection of ECs might also be affected by the mechanics of the host ECs, the latter being influenced by the stiffness of the matrix on which ECs reside. To test this hypothesis, we developed a novel multi-well format assay that allows assessing in a highly quantitative manner the differential effect of matrix stiffness on EC bacterial infection. We demonstrate that, using our assay, we can quantify infection efficiency through flow cytometry and microscopy, and also measure the effects of infection on EC mechanics through traction force microscopy. Our method allows for the analysis of the effect of tissue-relevant mechanics on EC infection, which is a critical step towards understanding the biomechanical interactions between ECs, their extracellular matrix and pathogenic bacteria.
    Full-text · Article · Oct 2016 · Toxins
    • "e study indicating up to 36% mortality rate associated with SA?mediated sepsis and meningitis (Aguilar et al., 2010). The SA surface is coated with a diverse range of proteins that work in conjunction with secreted virulence factors to enable the bacterium to adhere and to invade host cells, including vascular endothelial cells (Foster et al., 2014., Lemichez et al., 2010). The ability of SA to survive within mammalian host cells, either in the phagosome or freely in the cytosol, has also received considerable attention (Fraunholz & Sinha, 2012). To date however, our basic understanding of how SA specifically interacts with microvascular endothelial cells of the BBB to elicit barrier failure is still ver"
    [Show abstract] [Hide abstract] ABSTRACT: Blood-brain barrier (BBB) disruption constitutes a hallmark event during pathogen-mediated neurological disorders such as bacterial meningitis. As a prevalent opportunistic pathogen, Staphylococcus aureus (SA) is of particular interest in this context, although our fundamental understanding of how SA disrupts the BBB is very limited. This paper employs in vitro infection models to address this. Human brain microvascular endothelial cells (HBMvECs) were infected with formaldehyde-fixed (MOI 0-250, 0-48 hrs) and live (MOI 0-100, 0-3 hrs) SA cultures. Both Fixed-SA and Live-SA could adhere to HBMvECs with equal efficacy and cause elevated paracellular permeability. In further studies employing Fixed-SA, infection of HBMvECs caused dose-dependent release of cytokines/chemokines (TNF-α, IL-6, MCP-1, IP-10, thrombomodulin), reduced expression of interendothelial junction proteins (VE-Cadherin, claudin-5 and ZO-1), and activation of both canonical and non-canonical NF-κB pathways. Using N-acetylcysteine, we determined that these events were coupled to the SA-mediated induction of reactive oxygen species (ROS) within HBMvECs. Finally, treatment of HBMvECs with Fixed-ΔSpA (MOI 0-250, 48 hrs), a gene deletion mutant of Staphylococcal protein A (SpA) associated with bacterial infectivity, had relatively similar effects to Newman WT Fixed-SA. In conclusion, these findings provide insight into how S.aureus infection may activate proinflammatory mechanisms within the brain microvascular endothelium to elicit BBB failure.
    Full-text · Article · Sep 2016
    • "EDINs toxins are members of a group of major bacterial virulence factors targeting host Rho GTPases [167]. Recent findings suggest that EDIN toxins might favor bacterial dissemination in tissues by a hematogenous route, through the induction of large transcellular tunnels in endothelial cells named macroapertures [168][169][170]. Indeed, recent data showed that EDIN toxins promote the formation of infection foci in a mouse model of bacteremia [171]. "
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    Full-text · Article · Jul 2016
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