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.

  • Review Article
  • Published:

Mechanisms of microbial traversal of the blood–brain barrier

Nature Reviews Microbiology volume 6, pages 625–634 (2008)Cite this article

Key Points

  • Microbial invasion and traversal of the blood–brain barrier is a prerequisite for meningitis and the associated blood–brain barrier dysfunction. Our current knowledge has been charted using Escherichia coli, with an emphasis on similarities and differences between different pathogens.

  • Transcellular penetration of the blood–brain barrier has been demonstrated for most meningitis-causing microorganisms, but the underlying mechanisms differ for different organisms.

  • E. coli invasion of the blood–brain barrier requires a high level of bacteraemia, as well as several bacterial and host factors. These microorganism–host interactions are unique to the blood–brain barrier and the relevant interactions have begun to be identified for E. coli and other meningitis-causing microorganisms.

  • Microbial binding to, and invasion of, the blood–brain barrier occurs through ligand–receptor interactions. Different microbial ligands interact with the same receptors, but the relevant interactions that are involved in traversal of the blood–brain barrier remain incompletely understood.

  • Microbial invasion and traversal of the blood–brain barrier requires rearrangement of the host cell cytoskeleton. Different microorganisms use different signal-transduction mechanisms to effect this rearrangement.

  • Central nervous system-infecting microorganisms induce blood–brain barrier dysfunction, but the underlying mechanisms differ from those that are involved in microbial binding to or invasion of the blood–brain barrier.

Abstract

Central nervous system (CNS) infections continue to be an important cause of morbidity and mortality. Microbial invasion and traversal of the blood–brain barrier is a prerequisite for CNS infections. Pathogens can cross the blood–brain barrier transcellularly, paracellularly and/or in infected phagocytes (the so-called Trojan-horse mechanism). Consequently, pathogens can cause blood–brain barrier dysfunction, including increased permeability, pleocytosis and encephalopathy. A more complete understanding of the microbial–host interactions that are involved in microbial traversal of the blood–brain barrier and the associated barrier dysfunction should help to develop new strategies to prevent CNS infections.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: The blood–brain barrier.
Figure 2: Mechanisms involved in microbial traversal of the blood–brain barrier.
Figure 3: The effect of microbial determinants on Escherichia coli meningitis.
Figure 4: Signalling mechanisms involved in Escherichia coli K1-mediated actin cytoskeleton rearrangements and traversal of the blood–brain barrier.

Similar content being viewed by others

References

  1. World Health Organization. World health report: changing history (WHO, Geneva, 2004).

  2. Klinger, G., Chin, C.-N., Beyene, J. & Perlman, M. Predicting the outcome of neonatal bacterial meningitis. Pediatrics 106, 477–482 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Stevens, J. P. et al. Long-term outcome of neonatal meningitis. Arch. Dis. Child. Fetal Neonatal Ed. 88, F179–F184 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chang, C.-J. et al. Bacterial meningitis in infants: the epidemiology, clinical features, and prognostic factors. Brain Dev. 26, 168–175 (2004).

    Article  PubMed  Google Scholar 

  5. van de Beek, D. et al. Clinical features and prognostic factors in adults with bacterial meningitis. N. Engl. J. Med. 351, 1849–1859 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Kim, K. S. Pathogenesis of bacterial meningitis: from bacteraemia to neuronal injury. Nature Rev. Neurosci. 4, 376–385 (2003). A comprehensive review on the pathogenesis of meningitis and the associated neuronal injury.

    Article  CAS  Google Scholar 

  7. Kim, K. S. Microbial translocation of the blood–brain barrier. Int. J. Parasitol. 36, 607–614 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Kim, Y. V., Di Cello, F., Hillaire, C. S. & Kim, K. S. Differential Ca2+ signaling by thrombin and protease-activated receptor-1-activating peptide in human brain microvascular endothelial cells. Am. J. Physiol. Cell Physiol. 286, C31–C42 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Ruffer, C., Strey, A., Janning, A., Kim, K. S. & Gerke, V. Cell–cell junctions of dermal microvascular endothelial cells contain tight and adherens junction proteins in spatial proximity. Biochemistry 43, 5360–5369 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Stins, M. F., Badger, J. L. & Kim, K. S. Bacterial invasion and transcytosis in transfected human brain microvascular endothelial cells. Microb. Pathog. 30, 19–28 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Rubin, L. L. & Staddon, J. M. The cell biology of the blood–brain barrier. Annu. Rev. Neurosci. 22, 11–28 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Mucke, L. & Eddleston, M. Astrocytes in infectious and immune-mediated diseases of the central nervous system. FASEB J. 7, 1226–1232 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Daubener, W. et al. Restriction of Toxoplasma gondii growth in human brain microvascular endothelial cells by activation of indoleamine 2,3-dioxygenase. Infect. Immun. 69, 6527–6531 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Anfuso, C. D. et al. Endothelial cell–pericyte cocultures induce PLA2 protein expression through activation of PKCα and MAPK/ERK cascade. J. Lipid Res. 48, 782–793 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Stins, M. F., Gilles, F. & Kim, K. S. Selective expression of adhesion molecules on human brain microvascular endothelial cells. J. Neuroimmunol. 76, 81–90 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Das, A. et al. Differential role of cytosolic phospholipase A2 in the invasion of brain microvascular endothelial cells by Escherichia coli and Listeria monocytogenes. J. Infect. Dis. 184, 732–737 (2001). Described the contribution of cPLA2 to E. coli invasion of brain microvascular endothelial cells.

    Article  CAS  PubMed  Google Scholar 

  17. Kim, K. S. et al. The K1 capsule is the critical determinant in the development of Escherichia coli meningitis in the rat. J. Clin. Invest. 90, 897–905 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tan, T. Q., Smith, C. W., Hawkins, E. P., Mason, E. O. Jr & Kaplan, S. L. Hematogenous bacterial meningitis in an intercellular adhesion molecule-1-deficient infant mouse model. J. Infect. Dis. 171, 342 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. Munoz, F. M., Hawkins, E. P., Bullard, D. C., Beauchet, A. L. & Kaplan, S. L. Host defense against systemic infection with Streptococcus pneumoniae is impaired in E-, P-, and E-/P-selectin-deficient mice. J. Clin. Invest. 100, 2099–2106 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nizet, V. et al. Invasion of brain microvascular endothelial cells by group B streptococci. Infect. Immun. 65, 5074–5081 (1997). The first study to show transcellular penetration of HBMECs by S. agalactiae.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ring, A., Weiser, J. N. & Tuomanen, E. I. Pneumococcal trafficking across the blood–brain barrier. Molecular analysis of a novel bi-directional pathway. J. Clin. Invest. 102, 347–360 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Unkmeir, A. et al. Fibronectin mediates Opc-dependent internalization of Neisseria meningitidis in human brain microvascular endothelial cells. Mol. Microbiol. 46, 933–946 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Jong, A. Y., Stins, M. F., Huang, S. H. & Kim, K. S. Traversal of Candida albicans across human blood–brain barrier in vitro. Infect. Immun. 69, 4536–4544 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chang, Y. C. et al. Cryptococcal yeast cells invade the central nervous system via transcellular penetration of the blood–brain barrier. Infect. Immun. 72, 4985–4995 (2004). The first study to show transcellular penetration of the blood–brain barrier by C. neoformans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Masocha, W., Rottenberg, M. E. & Kristensson, K. Migration of African trypanosomes across the blood–brain barrier. Physiol. Behav. 92, 110–114 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Grab, D. J. et al. African trypanosome interactions with an in vitro model of the human blood–brain barrier. J. Parasitol. 90, 970–979 (2004).

    Article  PubMed  Google Scholar 

  27. Grab, D. et al. Borrelia burgdorferi, host-derived proteases, and the blood–brain barrier. Infect. Immun. 73, 1014–1022 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sethi, N., Sondey, M., Bai, Y., Kim, K. S. & Cadavid, D. Interaction of a neurotropic strain of Borrelia turicatae with the cerebral microcirculation system. Infect. Immun. 74, 6408–6418 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Drevets, D. A., Leenen P. J. & Greenfield, R. A. Invasion of the central nervous system by intracellular bacteria. Clin. Microbiol. Rev. 17, 323–347 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Greiffenberg, L., Goebel, W., Kim, K. S. & Kuhn, M. Interaction of Listeria monocytogenes with human brain microvascular endothelial cells: InlB-dependent invasion, long-term intracellular growth, and spread from macrophages to endothelial cells. Infect. Immun. 66, 5260–5267 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Jain, S. K., Paul-Satyaseela, M., Lamichhane, G., Kim, K. S. & Bishai, W. R. Mycobacterium tuberculosis invasion and traversal across an in vitro human blood–brain barrier as a pathogenic mechanism for central nervous system tuberculosis. J. Infect. Dis. 193, 1287–1295 (2006). The first paper to show transcellular penetration of HBMECs by M. tuberculosis.

    Article  CAS  PubMed  Google Scholar 

  32. Be, N. A. et al. Bacterial genetic determinants for Mycobacterium tuberculosis invasion and survival in the central nervous system. J. Infect. Dis. (in the press).

  33. Ferrieri, P., Burke, B. & Nelson, J. Production of bacteremia and meningitis in infant rats with group B streptococcal serotypes. Infect. Immun. 27, 1023–1032 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Berman, P. H. & Banker, B. Q. Neonatal meningitis. A clinical and pathological study of 29 cases. Pediatrics 38, 6–24 (1966).

    CAS  PubMed  Google Scholar 

  35. Kim, K. S. Effect of antimicrobial therapy for experimental infections due to group B streptococcus on mortality and clearance of bacteria. J. Infect. Dis. 155, 1233–1241 (1987).

    Article  CAS  PubMed  Google Scholar 

  36. Dietzman, D. E., Fischer, G. W. & Schoenknecht, F. D. Neonatal Escherichia coli septicemia — bacterial counts in blood. J. Pediatr. 85, 128–130 (1974).

    Article  CAS  PubMed  Google Scholar 

  37. Bell, L. M., Alpert, G., Campos, J. M. & Plotkin, S. A. Routine quantitative blood cultures in children with Haemophilus influenzae or Streptococcus pneumoniae bacteremia. Pediatrics 76, 901–904 (1985).

    CAS  PubMed  Google Scholar 

  38. Sullivan, T. D., LaScolea, L. J. & Neter, E. Relationship between the magnitude of bacteremia in children and the clinical disease. Pediatrics 69, 699–702 (1982).

    CAS  PubMed  Google Scholar 

  39. Marra, A. & Brigham, M. D. Streptococcus pneumoniae causes experimental meningitis following intranasal and otitis media infections via a nonhematogenous route. Infect. Immun. 69, 7318–7325 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. van Ginkle, F. W. et al. Pneumococcal carriage results in ganglioside-mediated olfactory tissue infection. Proc. Natl Acad. Sci. USA 24, 14363–14367 (2003).

    Article  CAS  Google Scholar 

  41. Cross, A. S., Kim, K. S., Wright, D. C., Sadoff, J. C. & Gemski, P. Role of lipopolysaccharide and capsule in the serum resistance of bacteremic strains of Escherichia coli. J. Infect. Dis. 154, 497–503 (1986).

    Article  CAS  PubMed  Google Scholar 

  42. Xie, Y. et al. Identification and characterization of Escherichia coli RS218-derived islands in the pathogenesis of E. coli meningitis. J. Infect. Dis. 194, 358–364 (2006). The first comparative genomics study to demonstrate that E. coli K1-derived genomic islands contribute to meningitis.

    Article  CAS  PubMed  Google Scholar 

  43. Whitney, C. G. et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N. Engl. J. Med. 348, 1737–1746 (2003).

    Article  PubMed  Google Scholar 

  44. Tsai, C. J., Griffin, M. R., Pekka Nuorti, J. & Grijalva, C. G. Changing epidemiology of pneumococcal meningitis after the introduction of pneumococcal conjugate vaccine in the United States. Clin. Infect. Dis. 46, 1664–1672 (2008).

    Article  PubMed  Google Scholar 

  45. Moore, M. R. et al. Population snapshot of emergent Streptococcus pneumoniae serotype 19A in the United States, 2005. J. Infect. Dis. 197, 1016–1027 (2008).

    Article  PubMed  Google Scholar 

  46. Borrow, R. & Miller, E. Long-term protection in children with meningococcal C conjugate vaccination: lessons learned. Expert Rev. Vaccines 5, 851–857 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Huang, S. H. et al. Escherichia coli invasion of brain microvascular endothelial cells in vitro and in vivo: molecular cloning and characterization of invasion gene ibe10. Infect. Immun. 63, 4470–4475 (1995). First identification of the E. coli gene that contributes to the invasion of HBMECs and penetration into the brain.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Huang, S. H. et al. Identification and characterization of an Escherichia coli invasion gene locus, ibeB, required for penetration of brain microvascular endothelial cells. Infect. Immun. 67, 2103–2109 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Khan, N. A. et al. Cytotoxic necrotizing factor-1 contributes to Escherichia coli K1 invasion of the central nervous system. J. Biol. Chem. 277, 15607–15612 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Wang, Y., Huang, S. H., Wass, C. & Kim, K. S. The gene locus yijP contributes to Escherichia coli K1 invasion of brain microvascular endothelial cells. Infect. Immun. 67, 4751–4756 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Wang, Y. & Kim, K. S. Role of OmpA and IbeB in Escherichia coli invasion of brain microvascular endothelial cells in vitro and in vivo. Pediatr. Res. 51, 559–563 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Prasadarao, N. V., Wass, C. A., Stins, M., Shimada, H. & Kim, K. S. Outer membrane protein A-promoted actin condensation of brain microvascular endothelial cells is required for Escherichia coli invasion. Infect. Immun. 67, 5775–5783 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Knodler, L. A., Celli, J. & Finlay, B. B. Pathogenic trickery: deception of host cell processes. Nature Rev. Mol. Cell Biol. 2, 578–588 (2001).

    Article  CAS  Google Scholar 

  54. Cossart, P. & Sansonetti, P. J. Bacterial invasion: the paradigms of enteroinvasive pathogens. Science 304, 242–248 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Reddy, M. A., Wass, C. A., Kim, K. S., Schlaepfer, D. D. & Prasadarao, N. V. Involvement of focal adhesion kinase in Escherichia coli invasion of human brain microvascular endothelial cells. Infect. Immun. 68, 6423–6430 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Reddy, M. A., Nemani, P. V., Wass, C. A. & Kim, K. S. Phosphatidylinositol 3-kinase activation and interaction with focal adhesion kinase in Escherichia coli K1 invasion of human brain microvascular endothelial cells. J. Biol. Chem. 275, 36769–36774 (2000). Showed for the first time that activation of FAK and phosphatidylinositol 3-kinase is required for E. coli K1 invasion of HBMECs.

    Article  CAS  PubMed  Google Scholar 

  57. Kim, K. J., Elliott, S. A., DiCello, F., Stins, M. F. & Kim, K. S. The K1 capsule modulates trafficking of E. coli-containing vacuoles and enhances intracellular bacterial survival in human brain microvascular endothelial cells. Cell. Microbiol. 5, 245–252 (2003). First demonstration of the role of the K1 capsule in the modulation of E. coli movement in HBMECs.

    Article  CAS  PubMed  Google Scholar 

  58. 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 

  59. Siddharthan, V., Kim, Y. V., Liu, S. & Kim, K. S. Human astrocytes/astrocyte conditioned medium and shear stress enhance the barrier properties of human brain microvascular endothelial cells. Brain Res. 1147, 39–50 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Stins, M. F. et al. Binding characteristics of S fimbriated Escherichia coli to isolated brain microvascular endothelial cells. Am. J. Pathol. 145, 1228–1236 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Prasadarao, N. V., Wass, C. A. & Kim, K. S. Endothelial cell GlcNAcβ1–4 GlcNAc epitopes for outer membrane protein A enhance traversal of Escherichia coli across the blood–brain barrier. Infect. Immun. 64, 154–160 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Charland, N. et al. Streptococcus suis serotype 2 interactions with human brain microvascular endothelial cells. Infect. Immun. 68, 637–643 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hoffmann, I., Eugene, E., Nassif, X., Couraud, P. & Bourdoulous, S. Activation of ErbB2 receptor tyrosine kinase supports invasion of endothelial cells by Neisseria meningitidis. J. Cell Biol. 155, 133–145 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Teng, C. H. et al. Escherichia coli K1 RS218 interacts with human brain microvascular endothelial cells via type 1 fimbria bacteria in the fimbriated state. Infect. Immun. 73, 2923–2931 (2005). Used DNA microarrays to identify type 1 fimbriae in E. coli that bind to HBMECs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Khan, N. A. et al. Outer membrane protein A and cytotoxic necrotizing factor-1 use diverse signaling mechanisms for Escherichia coli K1 invasion of human brain microvascular endothelial cells. Microb. Pathog. 35, 35–42 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Khan, N. A., Kim, Y., Shin, S. & Kim, K. S. FimH-mediated Escherichia coli K1 invasion of human brain microvascular endothelial cells. Cell. Microbiol. 9, 169–178 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Shin, S., Lu, G., Cai, M. & Kim, K. S. Escherichia coli outer membrane protein A adheres to human brain microvascular endothelial cells. Biochem. Biophys. Res. Commun. 330, 1199–1204 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Prasadarao, N. V. et al. Cloning and expression of the Escherichia coli K1 outer membrane protein A receptor, a gp96 homologue. Infect. Immun. 71, 1680–1688 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Cabanes, D. et al. Gp96 is a receptor for a novel Listeria monocytogenes virulence factor, Vip, a surface protein. EMBO J. 24, 2827–2838 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Teng, C.-H. et al. Effects of ompA deletion on expression of type 1 fimbriae in Escherichia coli K1 strain RS218 and on the association of E. coli with human brain microvascular endothelial cells. Infect. Immun. 74, 5609–5616 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Badger, J., Wass, C., Weissman, S. & Kim, K. S. Application of signature-tagged mutagenesis for identification of Escherichia coli K1 genes that contribute to invasion of human brain microvascular endothelial cells. Infect. Immun. 68, 5056–5061 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Huang, S.-H., Wan, Z.-S., Chen, Y.-H., Jong, A. Y. & Kim, K. S. Further characterization of Escherichia coli brain microvascular endothelial cell invasion gene ibeA by deletion, complementation, and protein expression. J. Infect. Dis. 183, 1071–1078 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Nemani, P. V., Wass, C. A., Huang, S.-H. & Kim, K. S. Identification and characterization of a novel Ibe10 binding protein that contributes to Escherichia coli invasion of brain microvascular endothelial cells. Infect. Immun. 67, 1131–1138 (1999).

    Google Scholar 

  75. Flatau, G. et al. Toxin-induced activation of the G protein p21 Rho by deamidation of glutamine. Nature 387, 729–733 (1997).

    Article  CAS  PubMed  Google Scholar 

  76. Schmidt, G. et al. Gln 63 of Rho is deamidated by Escherichia coli cytotoxic necrotizing factor-I. Nature 387, 725–729 (1997).

    Article  CAS  PubMed  Google Scholar 

  77. Contamin, S. et al. The p21 Rho-activating toxin cytotoxic necrotizing factor 1 is endocytosed by a clathrin-independent mechanism and enters the cytosol by an acidic-dependent membrane translocation step. Mol. Biol. Cell 11, 1775–1787 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chung, J. W. et al. 37-kDa laminin receptor precursor modulates cytotoxic necrotizing factor 1-mediated RhoA activation and bacterial uptake. J. Biol. Chem. 278, 16857–16862 (2003). The first study to identify 37 LRP as the receptor for CNF1.

    Article  CAS  PubMed  Google Scholar 

  79. Massia, S. P., Rao, S. S. & Hubbell, J. A. Covalently immobilized laminin peptide Tyr-Ile-Gly-Ser-Arg (YIGSR) supports cell spreading and co-localization of the 67-kilodalton laminin receptor with α-actinin and vinculin. J. Biol. Chem. 268, 8053–8059 (1993).

    CAS  PubMed  Google Scholar 

  80. Kim, K. J., Chung, J. W. & Kim, K. S. 67-kDa laminin receptor promotes internalization of cytotoxic necrotizing factor 1-expressing Escherichia coli K1 into human brain microvascular endothelial cells. J. Biol. Chem. 280, 1360–1368 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Ludwig, G. V., Kondig, J. P. & Smith, J. F. A putative receptor for Venezuelan equine encephalitis virus from mosquito cells. J. Virol. 70, 5592–5599 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Gauczynski, S. et al. The 37-kDa/67-kDa laminin receptor acts as the cell-surface receptor for the cellular prion protein. EMBO J. 20, 5863–5875 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Thepparit, C. & Smith, D. R. Serotype-specific entry of dengue virus into liver cells: identification of the 37-kilodalton/67-kilodalton high-affinity laminin receptor as a dengue virus serotype 1 receptor. J. Virol. 78, 12647–12656 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Akache, B. et al. The 37/67-kilodalton laminin receptor is a receptor for adeno-associated virus serotypes 8, 2, 3, and 9. J. Virol. 80, 9831–9836 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Tenenbaum, T. et al. Streptococcus agalactiae invasion of human brain microvascular endothelial cells is promoted by the laminin-binding protein Lmb. Microbes Infect. 9, 714–720 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Tenenbaum, T., Bloier, C., Adam, R., Reinscheid, D. J. & Schroten, H. Adherence to and invasion of human brain microvascular endothelial cells are promoted by fibrinogen-binding protein FbsA of Streptococcus agalactiae. Infect. Immun. 73, 4404–4409 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Doran, K. S. et al. Blood–brain barrier invasion by group B Streptococcus depends upon proper cell-surface anchoring of lipoteichoic acid. J. Clin. Invest. 115, 2499–2507 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Maisey, H. C., Hensler, M., Nizet, V. & Doran, K. S. Group B streptococcal pilus proteins contribute to adherence to and invasion of brain microvascular endothelial cells. J. Bacteriol. 189, 1464–1467 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Braun, L., Ghebrehiwet, B. & Cossart P. gC1q-R/p32, a C1q-binding protein, is a receptor for the InlB invasion protein of Listeria monocytogenes. EMBO J. 19, 1458–1466 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Shen, Y., Naujokas, M., Park, M. & Ireton, K. InIB-dependent internalization of Listeria is mediated by the Met receptor tyrosine kinase. Cell 103, 501–510 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Niemann, H. H. et al. Structure of the human receptor tyrosine kinase Met in complex with the Listeria invasion protein InIB. Cell 130, 235–246 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Biswas, A. K. et al. Plasmodium falciparum uses gC1qR/HABP1/p32 as a receptor to bind to vascular endothelium and for platelet-mediated clumping. PloS Pathog. 3, 1271–1280 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Cundell, D. R., Gerard, N. P., Gerard, C., Idanpaan-Heikkila, I. & Tuomanen, E. I. Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor. Nature 377, 435–438 (1995).

    Article  CAS  PubMed  Google Scholar 

  94. Radin, J. N. et al. β-arrestin 1 participates in platelet-activating factor receptor-mediated endocytosis of Streptococcus pneumoniae. Infect. Immun. 73, 7827–7835 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Weiser, J. N. et al. Phosphorylcholine on the lipopolysaccharide of Haemophilus influenzae contributes to persistence in the respiratory tract and sensitivity to serum killing mediated by C-reactive protein. J. Exp. Med. 187, 631–640 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cabellos, C. et al. Differing roles of platelet-activating factor during inflammation of the lung and subarachnoid space. The special case of Streptococcus pneumoniae. J. Clin. Invest. 90, 612–618 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Nassif, X., Pujol, C., Morand, P. & Eugene, E. Interactions of pathogenic Neisseria with host cells. Is it possible to assemble the puzzle? Mol. Microbiol. 32, 1124–1132 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Johansson, L. et al. CD46 in meningococcal disease. Science 301, 373–375 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Capecchi, B. et al. Neisseria meningitis NadA is a new invasin which promotes bacterial adhesion to and penetration into human epithelial cells. Mol. Microbiol. 55, 687–698 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Plant, L. et al. Lipooligosaccharide structure contributes to multiple steps in the virulence of Neisseria meningitidis. Infect. Immun. 74, 1360–1367 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Manchester, M. et al. Clinical isolates of measles virus use CD46 as a cellular receptor. J. Virol. 74, 3967–3974 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Gaggar, A., Shayakhmetov, D. M. & Lieber, A. CD46 is a cellular receptor for group B adenoviruses. Nature Med. 9, 1408–1412 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Santoro, F. et al. Interaction of glycoprotein H of human herpesvirus 6 with the cellular receptor CD46. J. Biol. Chem. 278, 25964–25969 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Rich, A. R. & McCordock, H. A. The pathogenesis of tuberculous meningitis. Bull. Johns Hopkins Hosp. 52, 5–37 (1933).

    Google Scholar 

  105. Thomas, D. D. et al. Treponema pallidum invades intercellular junctions of endothelial cell monolayers. Proc. Natl Acad. Sci. USA 85, 3608–3612 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhang, G. W., Khan, N. A., Kim, K. J., Stins, M. & Kim, K. S. Transforming growth factor-β increases Escherichia coli K1 adherence, invasion and transcytosis in human brain microvascular endothelial cells. Cell Tissue Res. 309, 281–286 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Galanakis, E., Di Cello, F., Paul-Satyaseela, M. & Kim, K. S. Escherichia coli K1 induces IL-8 expression in human brain microvascular endothelial cells. Eur. Cytokine Netw. 17, 260–265 (2006).

    CAS  PubMed  Google Scholar 

  108. Sokolova, O. et al. Interaction of Neisseria meningitidis with human brain microvascular endothelial cells: role of MAP- and tyrosine kinases in invasion and inflammatory cytokine release. Cell. Microbiol. 6, 1153–1166 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Tuomanen, E., Saukkonen, K., Sande, S., Cioffe, C. & Wright, S. D. Reduction of inflammation, tissue damage and mortality in bacterial meningitis in rabbits treated with monoclonal antibodies against adhesion-promoting receptors of leukocytes. J. Exp. Med. 170, 959–968 (1989).

    Article  CAS  PubMed  Google Scholar 

  110. Tauber, M. G., Borschberg, U. & Sande, M. A. Influence of granulocytes on brain edema, intracranial pressure, and cerebrospinal fluid concentrations of lactate and protein in experimental meningitis. J. Infect. Dis. 157, 456–464 (1988).

    Article  CAS  PubMed  Google Scholar 

  111. Lesse, A. J., Moxon, E. R., Zwahten, A. & Scheid, W. M. Role of cerebrospinal fluid pleocytosis and Haemophilus influenzae type b capsule on blood brain barrier permeability during experimental meningitis in the rat. J. Clin. Invest. 82, 102–109 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Vadeboncoeur, N., Segura, M., Al-Numani, D., Vanier, G. & Gottschalk, M. Pro-inflammatory cytokine and chemokine release by human brain microvascular endothelial cells stimulated by Streptococcus suis serotype 2. FEMS Immunol. Med. Microbiol. 35, 49–58 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Frigerio, S. et al. Immunocompetence of human microvascular brain endothelial cells: cytokine regulation of IL-1β, MCP-1, IL-10, sICAM-1 and sVCAM-1. J. Neurol. 245, 727–730 (1998).

    Article  CAS  PubMed  Google Scholar 

  114. Medana, I. M. & Turner, G. D. Human cerebral malaria and the blood–brain barrier. Int. J. Parasitol. 36, 555–568 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. van der Heyde, H. C., Nolan, J., Combes, V., Gramaglia, I. & Grau, G. E. A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction. Trends Parasitol. 22, 503–508 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. Tripathi, A. K., Sullivan, D. J. & Stins, M. F. Plasmodium falciparum-infected erythrocytes decrease the integrity of human blood–brain barrier endothelial cell monolayers. J. Infect. Dis. 195, 942–950 (2007).

    Article  PubMed  Google Scholar 

  117. Kugler, S. et al. Pertussis toxin transiently affects barrier integrity, organelle organization and transmigration of monocytes in a human brain microvascular endothelial cell barrier model. Cell. Microbiol. 9, 619–632 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Perfect, J. R. & Casadevall, A. Cryptococcus. Infect. Dis. Clin. North Am. 4, 837–874 (2002).

    Article  Google Scholar 

  119. Chretien, F. et al. Pathogenesis of cerebral Cryptococcus neoformans infection after fungemia. J. Infect. Dis. 4, 522–530 (2002).

    Article  Google Scholar 

  120. Olszewski, M. A. et al. Urease expression by Cryptococcus neoformans promotes microvascular sequestration, thereby enhancing central nervous system invasion. Am. J. Pathol. 164, 1761–1771 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Noverr, M. C., Williamson, P. R., Fajardo, R. S. & Huffnagle, G. B. CNLAC1 is required for extrapulmonary dissemination of Cryptococcus neoformans but not pulmonary persistence. Infect. Immun. 72, 1693–1699 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Noveer, M. C., Cox, G. M., Perfect, J. R. & Huffnagle, G. B. Role of PLB1 in pulmonary inflammation and cryptococcal eicosanoid production. Infect. Immun. 71, 1538–1547 (2003).

    Article  CAS  Google Scholar 

  123. Santangelo, R. et al. Role of extracellular phospholipases and mononuclear phagocytes in dissemination of cryptococcosis in a murine model. Infect. Immun. 72, 2229–2239 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Shea, J. M., Kechichian, T. B., Luberto, C. & Del Poeta, M. The cryptococcal enzyme inositol phosphosphingolipid-phospholipase C confers resistance to the antifungal effects of macrophages and promotes fungal dissemination to the central nervous system. Infect. Immun. 74, 5977–5988 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The information contained in this Review is derived from studies carried out by members of the author's laboratory and his collaborators' laboratories. Work in the laboratory of K.S.K. was supported by National Institutes of Health grants.

Author information

Authors and Affiliations

  1. Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, 200 North Wolfe Street, Room 3157, Baltimore, 21287, Maryland, USA

    Kwang Sik Kim

Authors
  1. Kwang Sik Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

Entrez Genome Project

Borrelia burgdorferi

Borrelia turicatae

Candida albicans

Cryptococcus neoformans

Escherichia coli

Haemophilus influenzae

Listeria monocytogenes

Mycobacterium smegmatis

Mycobacterium tuberculosis

Neisseria meningitidis

Plasmodium falciparum

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus suis

Toxoplasma gondii

Treponema pallidum

Entrez Protein

CNF1

FbsA

IbeA

IbeB

IL-8

InlB

Lmb

NadA

OmpA

Glossary

Astrocyte

A star-shaped glial cell that supports the tissue of the central nervous system.

Pericyte

A cell that is found around capillaries and is related to smooth muscle cells. Pericytes surround the endothelium as single cells. Association with pericytes reduces endothelial apoptosis and stabilizes the vasculature.

Pinocytosis

The cellular uptake of extracellular fluid. Involves the formation of caveolae by the cell membrane that pinch off to form vesicles in the cytoplasm.

Microglial cell

An immune cell of the central nervous system that is derived from mesodermal precursor cells and could be of haematopoietic lineage.

Choroid plexus

A site of production of cerebrospinal fluid in the adult brain that is formed by the invagination of ependymal cells into the ventricles, which then become vascularized.

AB-type toxin

A bacterial toxin that modifies target proteins within the cytosol of host cells and is composed of two domains: one that is responsible for the enzymatic activity (A) and one that is responsible for cell-receptor binding (B).

Pleocytosis

The presence of a higher than normal number of cells in the cerebrospinal fluid.

Fibrinolytic system

A broad spectrum of proteolytic enzymes that includes the plasminogen activator system and plasmin. Plasmin and plasmin activators proteolytically degrade the extracellular matrix.

Encephalopathy

Brain dysfunction that is associated with alterations of the neural microenvironment and results from metabolic, toxic, vascular, infectious and/or inflammatory insults.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, K. Mechanisms of microbial traversal of the blood–brain barrier. Nat Rev Microbiol 6, 625–634 (2008). https://doi.org/10.1038/nrmicro1952

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro1952

This article is cited by

Search

Advanced 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