Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Breaking the wall: targeting of the endothelium by pathogenic bacteria

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.

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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

Similar content being viewed by others

References

  1. Valbuena, G. & Walker, D. H. The endothelium as a target for infections. Annu. Rev. Pathol. 1, 171–198 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Wolinsky, H. A proposal linking clearance of circulating lipoproteins to tissue metabolic activity as a basis for understanding atherogenesis. Circ. Res. 47, 301–311 (1980).

    Article  CAS  PubMed  Google Scholar 

  3. Aird, W. C. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ. Res. 100, 158–173 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Aird, W. C. Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ. Res. 100, 174–190 (2007). References 3 and 4 are thorough reviews on endothelium structure, heterogeneity and function.

    Article  CAS  PubMed  Google Scholar 

  5. Bazzoni, G. & Dejana, E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol. Rev. 84, 869–901 (2004).

    CAS  PubMed  Google Scholar 

  6. Aird, W. C. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101, 3765–3777 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Angus, D. C. et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 29, 1303–1310 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Campbell, L. A. & Kuo, C. C. Chlamydia pneumoniae — an infectious risk factor for atherosclerosis? Nature Rev. Microbiol. 2, 23–32 (2004).

    Article  CAS  Google Scholar 

  9. Aird, W. C. Endothelium as a therapeutic target in sepsis. Curr. Drug Targets 8, 501–507 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Wojciak-Stothard, B. & Ridley, A. J. Rho GTPases and the regulation of endothelial permeability. Vascul. Pharmacol. 39, 187–199 (2003).

    Article  CAS  Google Scholar 

  11. Carman, C. V. & Springer, T. A. Trans-cellular migration: cell-cell contacts get intimate. Curr. Opin. Cell Biol. 20, 533–540 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rittirsch, D., Flierl, M. A. & Ward, P. A. Harmful molecular mechanisms in sepsis. Nature Rev. Immunol. 8, 776–787 (2008).

    Article  CAS  Google Scholar 

  13. Pegu, A. et al. Human lymphatic endothelial cells express multiple functional TLRs. J. Immunol. 180, 3399–3405 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Loos, T. et al. TLR ligands and cytokines induce CXCR3 ligands in endothelial cells: enhanced CXCL9 in autoimmune arthritis. Lab. Invest. 86, 902–916 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Kawai, T. & Akira, S. Signaling to NF-κB by Toll-like receptors. Trends Mol. Med. 13, 460–469 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Brodsky, I. E. & Medzhitov, R. Targeting of immune signalling networks by bacterial pathogens. Nature Cell Biol. 11, 521–526 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Jaffe, A. B. & Hall, A. RHO GTPases: biochemistry and biology. Annu. Rev. Cell Dev. Biol. 21, 247–269 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Boquet, P. & Lemichez, E. Bacterial virulence factors targeting Rho GTPases: parasitism or symbiosis? Trends Cell Biol. 13, 238–246 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Munro, P. et al. Activation and proteasomal degradation of Rho GTPases by cytotoxic necrotizing factor-1 elicit a controlled inflammatory response. J. Biol. Chem. 279, 35849–35857 (2004). DNA macroarray analysis of the inflammatory responses that are induced in endothelial cells through direct activation of Rho GTPases by CNF1 of pathogenic E. coli .

    Article  CAS  PubMed  Google Scholar 

  20. Bokoch, G. M. Regulation of innate immunity by Rho GTPases. Trends Cell Biol. 15, 163–171 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Xie, Y., Kim, K. J. & Kim, K. S. Current concepts on Escherichia coli K1 translocation of the blood-brain barrier. FEMS Immunol. Med. Microbiol. 42, 271–279 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Miller, S. I., Ernst, R. K. & Bader, M. W. LPS, TLR4 and infectious disease diversity. Nature Rev. Microbiol. 3, 36–46 (2005).

    Article  CAS  Google Scholar 

  23. Fraser, J. D. & Proft, T. The bacterial superantigen and superantigen-like proteins. Immunol. Rev. 225, 226–243 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Lorenz, E., Mira, J. P., Frees, K. L. & Schwartz, D. A. Relevance of mutations in the TLR4 receptor in patients with Gram-negative septic shock. Arch. Intern. Med. 162, 1028–1032 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Wang, L. et al. Crystal structure of a complete ternary complex of TCR, superantigen and peptide-MHC. Nature Struct. Mol. Biol. 14, 169–171 (2007).

    Article  CAS  Google Scholar 

  26. Hotchkiss, R. S. & Nicholson, D. W. Apoptosis and caspases regulate death and inflammation in sepsis. Nature Rev. Immunol. 6, 813–822 (2006).

    Article  CAS  Google Scholar 

  27. Arbibe, L. & Sansonetti, P. J. Epigenetic regulation of host response to LPS: causing tolerance while avoiding Toll errancy. Cell Host Microbe 1, 244–246 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Brown, K. A. et al. Neutrophils in development of multiple organ failure in sepsis. Lancet 368, 157–169 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Clark, S. R. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nature Med. 13, 463–469 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004). The first report of NETs.

    Article  CAS  PubMed  Google Scholar 

  31. Beiter, K. et al. An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Curr. Biol. 16, 401–407 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Kozek-Langenecker, S. A., Spiss, C. K., Michalek-Sauberer, A., Felfernig, M. & Zimpfer, M. Effect of prostacyclin on platelets, polymorphonuclear cells, and heterotypic cell aggregation during hemofiltration. Crit. Care Med. 31, 864–868 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Kessenbrock, K. et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nature Med. 15, 623–625 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Esmon, C. T. The interactions between inflammation and coagulation. Br. J. Haematol. 131, 417–430 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Niessen, F. et al. Dendritic cell PAR1–S1P3 signalling couples coagulation and inflammation. Nature 452, 654–658 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Faust, S. N. et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N. Engl. J. Med. 345, 408–416 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Levi, M., de Jonge, E. & van der Poll, T. New treatment strategies for disseminated intravascular coagulation based on current understanding of the pathophysiology. Ann. Med. 36, 41–49 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Mullarky, I. K. et al. Infection-stimulated fibrin deposition controls hemorrhage and limits hepatic bacterial growth during listeriosis. Infect. Immun. 73, 3888–3895 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kastrup, C. J. et al. Spatial localization of bacteria controls coagulation of human blood by 'quorum acting'. Nature Chem. Biol. 4, 742–750 (2008). This work shows that clustering of some pathogenic bacteria can produce enough factors to directly activate the coagulation of human blood.

    Article  CAS  Google Scholar 

  40. Mairey, E. et al. Cerebral microcirculation shear stress levels determine Neisseria meningitidis attachment sites along the blood-brain barrier. J. Exp. Med. 203, 1939–1950 (2006). The first demonstration that the force exerted by the blood flow can determine bacterial attachment sites along human vasculature.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kim, K. S. Mechanisms of microbial traversal of the blood-brain barrier. Nature Rev. Microbiol. 6, 625–634 (2008). A recent review that discusses the possible mechanisms by which a pathogen can invade the brain.

    Article  CAS  Google Scholar 

  42. Disson, O. et al. Conjugated action of two species-specific invasion proteins for fetoplacental listeriosis. Nature 455, 1114–1118 (2008). This study finds that the combined action of species-specific bacterial adhesion molecules is required for the development of fetoplacental listeriosis.

    Article  CAS  PubMed  Google Scholar 

  43. van Deuren, M., Brandtzaeg, P. & van der Meer, J. W. Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin. Microbiol. Rev. 13, 144–166 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Virji, M. et al. The role of pili in the interactions of pathogenic Neisseria with cultured human endothelial cells. Mol. Microbiol. 5, 1831–1841 (1991).

    Article  CAS  PubMed  Google Scholar 

  45. Nassif, X. et al. Roles of pilin and PilC in adhesion of Neisseria meningitidis to human epithelial and endothelial cells. Proc. Natl Acad. Sci. USA 91, 3769–3773 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Virji, M. Pathogenic neisseriae: surface modulation, pathogenesis and infection control. Nature Rev. Microbiol. 7, 274–286 (2009). A comprehensive review of pathogenic neisseria, examining the known mechanisms used by these pathogens for niche establishment and the challenges that such mechanisms pose for infection control.

    Article  CAS  Google Scholar 

  47. Kirchner, M., Heuer, D. & Meyer, T. F. CD46-independent binding of neisserial type IV pili and the major pilus adhesin, PilC, to human epithelial cells. Infect. Immun. 73, 3072–3082 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Merz, A. J., So, M. & Sheetz, M. P. Pilus retraction powers bacterial twitching motility. Nature 407, 98–102 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Maier, B., Koomey, M. & Sheetz, M. P. A force-dependent switch reverses type IV pilus retraction. Proc. Natl Acad. Sci. USA 101, 10961–10966 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hoffmann, I., Eugene, E., Nassif, X., Couraud, P. O. & Bourdoulous, S. Activation of ErbB2 receptor tyrosine kinase supports invasion of endothelial cells by Neisseria meningitidis. J. Cell Biol. 155, 133–143 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Eugene, E. et al. Microvilli-like structures are associated with the internalization of virulent capsulated Neisseria meningitidis into vascular endothelial cells. J. Cell Sci. 115, 1231–1241 (2002).

    CAS  PubMed  Google Scholar 

  52. Lambotin, M. et al. Invasion of endothelial cells by Neisseria meningitidis requires cortactin recruitment by a PI3-Kinase/Rac1 signalling pathway triggered by the lipo-oligosaccharide. J. Cell Sci. 118, 3805–3816 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Doulet, N. et al. Neisseria meningitidis infection of human endothelial cells interferes with leukocyte transmigration by preventing the formation of endothelial docking structures. J. Cell Biol. 173, 627–637 (2006). The first demonstration that bacterial pathogens can hamper the triggering of host inflammatory responses by affecting the interaction of leukocytes with endothelial cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lambotin, M. et al. Invasion of endothelial cells by Neisseria meningitidis requires cortactin recruitment by a phosphoinositide-3-kinase/Rac1 signalling pathway triggered by the lipo-oligosaccharide. J. Cell Sci. 118, 3805–3816 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Nassif, X., Bourdoulous, S., Eugene, E. & Couraud, P. O. How do extracellular pathogens cross the blood-brain barrier? Trends Microbiol. 10, 227–232 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Mikaty, G. et al. Neisseria meningitidis-induced host cell surface reorganization confers mechanical resistance to bacterial microcolonies in the bloodstream. PLoS Pathog. (in the press).

  57. Nikulin, J., Panzner, U., Frosch, M. & Schubert-Unkmeir, A. Intracellular survival and replication of Neisseria meningitidis in human brain microvascular endothelial cells. Int. J. Med. Microbiol. 296, 553–558 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Pujol, C., Eugene, E., de Saint Martin, L. & Nassif, X. Interaction of Neisseria meningitidis with a polarized monolayer of epithelial cells. Infect. Immun. 65, 4836–4842 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Weksler, B. B. et al. Blood-brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J. 19, 1872–1874 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Coureuil, M. et al. Meningococcal type IV pili recruit the polarity complex to cross the brain endothelium. Science 325, 83–87 (2009). This study elegantly shows how a bacterial pathogen may affect endothelial junction integrity by subverting the polarity complex.

    Article  CAS  PubMed  Google Scholar 

  61. Hurd, T. W., Gao, L., Roh, M. H., Macara, I. G. & Margolis, B. Direct interaction of two polarity complexes implicated in epithelial tight junction assembly. Nature Cell Biol. 5, 137–142 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Matter, K., Aijaz, S., Tsapara, A. & Balda, M. S. Mammalian tight junctions in the regulation of epithelial differentiation and proliferation. Curr. Opin. Cell Biol. 17, 453–458 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Bestebroer, J. et al. Staphylococcal SSL5 inhibits leukocyte activation by chemokines and anaphylatoxins. Blood 113, 328–337 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Bestebroer, J. et al. Staphylococcal superantigen-like 5 binds PSGL-1 and inhibits P-selectin-mediated neutrophil rolling. Blood 109, 2936–2943 (2007).

    CAS  PubMed  Google Scholar 

  65. Ley, K., Laudanna, C., Cybulsky, M. I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nature Rev. Immunol. 7, 678–689 (2007).

    Article  CAS  Google Scholar 

  66. Yamasaki, O. et al. Distribution of the exfoliative toxin D gene in clinical Staphylococcus aureus isolates in France. Clin. Microbiol. Infect. 12, 585–588 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Czech, A. et al. Prevalence of Rho-inactivating epidermal cell differentiation inhibitor toxins in clinical Staphylococcus aureus isolates. J. Infect. Dis. 184, 785–788 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Boyer, L. et al. Induction of transient macroapertures in endothelial cells through RhoA inhibition by Staphylococcus aureus factors. J. Cell Biol. 173, 809–819 (2006). The first report of the induction of transient transcellular tunnels (macroapertures) in endothelial cells as a consequence of a decrease in RHOA activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Schwarz-Linek, U. et al. Pathogenic bacteria attach to human fibronectin through a tandem β-zipper. Nature 423, 177–181 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Schroder, A. et al. Staphylococcus aureus fibronectin binding protein-A induces motile attachment sites and complex actin remodeling in living endothelial cells. Mol. Biol. Cell 17, 5198–5210 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Tuomanen, E. Entry of pathogens into the central nervous system. FEMS Microbiol. Rev. 18, 289–299 (1996).

    Article  CAS  PubMed  Google Scholar 

  72. Finlay, B. B. & Cossart, P. Exploitation of mammalian host cell functions by bacterial pathogens. Science 276, 718–725 (1997).

    Article  CAS  PubMed  Google Scholar 

  73. Walker, D. H. & Ismail, N. Emerging and re-emerging rickettsioses: endothelial cell infection and early disease events. Nature Rev. Microbiol. 6, 375–386 (2008).

    Article  CAS  Google Scholar 

  74. Voth, D. E. et al. The Coxiella burnetii ankyrin repeat domain-containing protein family is heterogeneous with C-terminal truncations that influence Dot/Icm-mediated secretion. J. Bacteriol. 191, 4232–4242 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Scheidegger, F. et al. Distinct activities of Bartonella henselae type IV secretion effector proteins modulate capillary-like sprout formation. Cell. Microbiol. 11, 1088–1101 (2009). This paper outlines a new model that allows the study of the molecular events underlying B. henselae -triggered angiogenesis.

    Article  CAS  PubMed  Google Scholar 

  76. Relman, D. A., Loutit, J. S., Schmidt, T. M., Falkow, S. & Tompkins, L. S. The agent of bacillary angiomatosis. An approach to the identification of uncultured pathogens. N. Engl. J. Med. 323, 1573–1580 (1990).

    Article  CAS  PubMed  Google Scholar 

  77. Dehio, C. Bartonella-host-cell interactions and vascular tumour formation. Nature Rev. Microbiol. 3, 621–631 (2005).

    Article  CAS  Google Scholar 

  78. Drancourt, M. et al. New serotype of Bartonella henselae in endocarditis and cat-scratch disease. Lancet 347, 441–443 (1996).

    Article  CAS  PubMed  Google Scholar 

  79. Kaiser, P. O. et al. The head of Bartonella adhesin A is crucial for host cell interaction of Bartonella henselae. Cell. Microbiol. 10, 2223–2234 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Szczesny, P. et al. Structure of the head of the Bartonella adhesin BadA. PLoS Pathog. 4, e1000119 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Manders, S. M. Bacillary angiomatosis. Clin. Dermatol. 14, 295–299 (1996).

    Article  CAS  PubMed  Google Scholar 

  82. Kyme, P. A. et al. Unusual trafficking pattern of Bartonella henselae-containing vacuoles in macrophages and endothelial cells. Cell. Microbiol. 7, 1019–1034 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Dehio, C., Meyer, M., Berger, J., Schwarz, H. & Lanz, C. Interaction of Bartonella henselae with endothelial cells results in bacterial aggregation on the cell surface and the subsequent engulfment and internalisation of the bacterial aggregate by a unique structure, the invasome. J. Cell Sci. 110, 2141–2154 (1997). A description of Bartonella -induced cell membrane reorganization into invasome structures.

    CAS  PubMed  Google Scholar 

  84. Rhomberg, T. A., Truttmann, M. C., Guye, P., Ellner, Y. & Dehio, C. A translocated protein of Bartonella henselae interferes with endocytic uptake of individual bacteria and triggers uptake of large bacterial aggregates via the invasome. Cell. Microbiol. 11, 927–945 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Kempf, V. A. et al. Evidence of a leading role for VEGF in Bartonella henselae-induced endothelial cell proliferations. Cell. Microbiol. 3, 623–632 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Kempf, V. A. et al. Activation of hypoxia-inducible factor-1 in bacillary angiomatosis: evidence for a role of hypoxia-inducible factor-1 in bacterial infections. Circulation 111, 1054–1062 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Schmid, M. C. et al. A translocated bacterial protein protects vascular endothelial cells from apoptosis. PLoS Pathog. 2, e115 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Johnson, K. E., Thorpe, C. M. & Sears, C. L. The emerging clinical importance of non-O157 Shiga toxin-producing Escherichia coli. Clin. Infect. Dis. 43, 1587–1595 (2006).

    Article  PubMed  Google Scholar 

  89. Karmali, M. A. et al. Association of genomic O island 122 of Escherichia coli EDL 933 with verocytotoxin-producing Escherichia coli seropathotypes that are linked to epidemic and/or serious disease. J. Clin. Microbiol. 41, 4930–4940 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. O'Brien, A. D. & Holmes, R. K. Shiga and Shiga-like toxins. Microbiol. Rev. 51, 206–220 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Romer, W. et al. Shiga toxin induces tubular membrane invaginations for its uptake into cells. Nature 450, 670–675 (2007). This article details a new mode of entry of Shiga toxin by self-induced membrane tubulation.

    Article  PubMed  CAS  Google Scholar 

  92. Warnier, M. et al. Trafficking of Shiga toxin/Shiga-like toxin-1 in human glomerular microvascular endothelial cells and human mesangial cells. Kidney Int. 70, 2085–2091 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Paton, A. W., Srimanote, P., Talbot, U. M., Wang, H. & Paton, J. C. A new family of potent AB5 cytotoxins produced by Shiga toxigenic Escherichia coli. J. Exp. Med. 200, 35–46 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Karch, H. et al. New aspects in the pathogenesis of enteropathic hemolytic uremic syndrome. Semin. Thromb. Hemost. 32, 105–112 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Wolfson, J. J. et al. Subtilase cytotoxin activates PERK, IRE1 and ATF6 endoplasmic reticulum stress-signalling pathways. Cell. Microbiol. 10, 1775–1786 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Byres, E. et al. Incorporation of a non-human glycan mediates human susceptibility to a bacterial toxin. Nature 456, 648–652 (2008). The discovery of the host cell receptor for SubAB of STEC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Aktories, K. & Barbieri, J. T. Bacterial cytotoxins: targeting eukaryotic switches. Nature Rev. Microbiol. 3, 397–410 (2005).

    Article  CAS  Google Scholar 

  98. Geny, B. et al. Clostridium sordellii lethal toxin kills mice by inducing a major increase in lung vascular permeability. Am. J. Pathol. 170, 1003–1017 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kirby, J. E. Anthrax lethal toxin induces human endothelial cell apoptosis. Infect. Immun. 72, 430–439 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Warfel, J. M., Steele, A. D. & D'Agnillo, F. Anthrax lethal toxin induces endothelial barrier dysfunction. Am. J. Pathol. 166, 1871–1881 (2005). This article reports lethal toxin of B. anthracis cleaves MAP kinase kinases to directly trigger the actin cytoskeleton reorganization that is responsible for an increase in endothelium permeability in human microvascular endothelial cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gozes, Y., Moayeri, M., Wiggins, J. F. & Leppla, S. H. Anthrax lethal toxin induces ketotifen-sensitive intradermal vascular leakage in certain inbred mice. Infect. Immun. 74, 1266–1272 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Alfano, R. W. et al. Potent inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin: implications for broad anti-tumor efficacy. Cell Cycle 7, 745–749 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Moayeri, M. & Leppla, S. H. The roles of anthrax toxin in pathogenesis. Curr. Opin. Microbiol. 7, 19–24 (2004).

    Article  CAS  PubMed  Google Scholar 

  104. Bradley, K. A., Mogridge, J., Mourez, M., Collier, R. J. & Young, J. A. Identification of the cellular receptor for anthrax toxin. Nature 414, 225–229 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Scobie, H. M., Rainey, G. J., Bradley, K. A. & Young, J. A. Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor. Proc. Natl Acad. Sci. USA 100, 5170–5174 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bonuccelli, G. et al. ATR/TEM8 is highly expressed in epithelial cells lining Bacillus anthracis' three sites of entry: implications for the pathogenesis of anthrax infection. Am. J. Physiol. Cell Physiol. 288, C1402–C1410 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Rmali, K. A., Al-Rawi, M. A., Parr, C., Puntis, M. C. & Jiang, W. G. Upregulation of tumour endothelial marker-8 by interleukin-1β and its impact in IL-1β induced angiogenesis. Int. J. Mol. Med. 14, 75–80 (2004).

    CAS  PubMed  Google Scholar 

  108. Abrami, L., Leppla, S. H. & van der Goot, F. G. Receptor palmitoylation and ubiquitination regulate anthrax toxin endocytosis. J. Cell Biol. 172, 309–320 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sun, J., Lang, A. E., Aktories, K. & Collier, R. J. Phenylalanine-427 of anthrax protective antigen functions in both pore formation and protein translocation. Proc. Natl Acad. Sci. USA 105, 4346–4351 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Duesbery, N. S. et al. Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science 280, 734–737 (1998).

    Article  CAS  PubMed  Google Scholar 

  111. Moayeri, M., Haines, D., Young, H. A. & Leppla, S. H. Bacillus anthracis lethal toxin induces TNF-α-independent hypoxia-mediated toxicity in mice. J. Clin. Invest. 112, 670–682 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Rolando, M. et al. Injection of Staphylococcus aureus EDIN by the Bacillus anthracis protective antigen machinery induces vascular permeability. Infect. Immun. 77, 3596–3601 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Bhavsar, A. P., Guttman, J. A. & Finlay, B. B. Manipulation of host-cell pathways by bacterial pathogens. Nature 449, 827–834 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Bone, R. C. et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 101, 1644–1655 (1992).

    Article  CAS  PubMed  Google Scholar 

  115. Voth, D. E. & Heinzen, R. A. Coxiella type IV secretion and cellular microbiology. Curr. Opin. Microbiol. 12, 74–80 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Merz, A. J. & So, M. Interactions of pathogenic Neisseriae with epithelial cell membranes. Annu. Rev. Cell Dev. Biol. 16, 423–457 (2000).

    Article  CAS  PubMed  Google Scholar 

  117. Bretscher, A., Edwards, K. & Fehon, R. G. ERM proteins and merlin: integrators at the cell cortex. Nature Rev. Mol. Cell Biol. 3, 586–599 (2002).

    Article  CAS  Google Scholar 

  118. Weed, S. A. & Parsons, J. T. Cortactin: coupling membrane dynamics to cortical actin assembly. Oncogene 20, 6418–6434 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Selbach, M. & Backert, S. Cortactin: an Achilles' heel of the actin cytoskeleton targeted by pathogens. Trends Microbiol. 13, 181–189 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network. Nature Rev. Mol. Cell Biol. 2, 127–137 (2001).

    Article  CAS  Google Scholar 

  121. Ge, Z., Schauer, D. B. & Fox, J. G. In vivo virulence properties of bacterial cytolethal-distending toxin. Cell. Microbiol. 10, 1599–1607 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Shenker, B. J. et al. A novel mode of action for a microbial-derived immunotoxin: the cytolethal distending toxin subunit B exhibits phosphatidylinositol 3,4,5-triphosphate phosphatase activity. J. Immunol. 178, 5099–5108 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Lemonnier, M., Landraud, L. & Lemichez, E. Rho GTPase-activating bacterial toxins: from bacterial virulence regulation to eukaryotic cell biology. FEMS Microbiol. Rev. 31, 515–534 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Vogelsgesang, M., Pautsch, A. & Aktories, K. C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins. Naunyn Schmiedebergs Arch. Pharmacol. 374, 347–360 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Popoff, M. R. et al. Ras, Rap, and Rac small GTP-binding proteins are targets for Clostridium sordellii lethal toxin glucosylation. J. Biol. Chem. 271, 10217–10224 (1996).

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Emmanuel Lemichez.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Supplementary information

41579_2010_BFnrmicro2269_MOESM1_ESM.mov

Supplementary information S1 | The movie shows the dynamics of opening and closure of macroapertures in human umbilical vein endothelial cells intoxicated by EDIN filmed by differential interference contrast. (MOV 4927 kb)

41579_2010_BFnrmicro2269_MOESM2_ESM.pdf

Glossary

Atherogenesis

The process of atheromatous plaque formation during atherosclerosis.

Inflammatory storm

An unspecific and massive release of inflammatory mediators.

Toxic shock syndrome

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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). https://doi.org/10.1038/nrmicro2269

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro2269

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing