Breaking the wall: targeting of the endothelium by pathogenic bacteria

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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.

Key Points

  • The targeting of the endothelium by bacteria and their toxins can produce severe pathologies, including: sepsis; endocarditis and focal vascular infections; septicaemia and ensuing septic metastasis and visceral abscesses; focal complications of bloodborne infections such as arthritis, meningitis and fetoplacental infections; and chronic infections leading to the formation of atherogenic or neo-angiogenic lesions.

  • Deregulation of innate immune responses by bacteria entering the cardiovascular system, combined with host susceptibility, can trigger systemic inflammatory syndrome, which damages the endothelium and can lead to immunoparalysis. Recent progress shows that neutrophil activation by platelets damages the endothelium.

  • Endothelial cells actively contribute to haemostatic homeostasis. Deregulation of this homeostasis by bloodborne pathogens can favour thrombosis and purpura fulminans. Recent work shows that some pathogenic bacteria can directly initiate the coagulation cascade.

  • Bacteria such as meningococci bind to and manipulate receptors at the endothelial cell surface to foster bacterial adhesion, circumvent shear stress forces that are exerted by the blood flow, recruit the polarity complex and destabilize intercellular junctions to disseminate in tissues.

  • Pathogenic bacteria trigger major endothelial cell membrane reorganizations, as do leukocytes during transcellular diapedesis across the endothelium. These reorganizations include the formation of transcellular tunnels that are induced by epidermal-cell differentiation inhibitor (EDIN) of Staphylococcus aureus and the formation of large membrane projections or invasomes in the case of Bartonella henselae.

  • Several toxins of pathogenic bacteria can hijack host inflammatory responses as well as the endothelial barrier function, inducing direct cytotoxic effects on the actin cytoskeleton and the endothelial cell.

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Figure 1: Stuctural features of the endothelial barrier.
Figure 2: Toxins and pathogens that target the endothelium.
Figure 3: Neisseria meningitidis.

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Acknowledgements

We apologize to all those authors in the field whose papers we could not cite because of space limitations. We thank L. Landraud and C. Dehio for discussions and N. Gauthier for the supplementary movie. We are supported by institutional funding from INSERM. Research in the E.L. laboratory is also supported by a grant from the Agence Nationale de la Recherche (ANR; grant RPV07055ASA) and the Association pour la Recherche sur le Cancer (ARC; grant 3800). Research in the S.B. and X.N. laboratories is also funded by grants from ANR and ARC. is M.L. is also funded by Institut Pasteur, ANR and FRM.

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Correspondence to Emmanuel Lemichez.

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Septic shock manifestations that are induced by bacterial toxins.

Extrinsic pathway

The primary pathway for the initiation of blood coagulation, triggered by a thrombin burst; this is also called the tissue factor pathway.

Intrinsic pathway

A secondary pathway for the initiation of blood coagulation that is classically triggered by contact activation of factor XII when blood comes into contact with negatively charged surfaces (potentially collagens); this is also called the contact activation pathway.

Extravasation

The exit of leukocytes from the blood stream.

Transendothelial diapedesis

The proess by which leukocytes cross the endothelium through large tunnels that are formed in endothelial cells.

Leukocyte rolling

The method by which loosely attached leukocytes at the surface of the endothelium move.

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Lemichez, E., Lecuit, M., Nassif, X. et al. Breaking the wall: targeting of the endothelium by pathogenic bacteria. Nat Rev Microbiol 8, 93–104 (2010) doi:10.1038/nrmicro2269

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