Key Points
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The blood–central nervous system (CNS) barriers are tight and protect the brain parenchyma from insults, including those of infectious origin. This barrier function is due to the presence of tight junctions between the endothelial cells of the brain. The formation of these junctions is the consequence of interactions inside the neurovascular unit.
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There are two blood–CNS barriers that can potentially be circumvented by bacterial pathogens: the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier (BCSFB). The BCSFB corresponds to the choroid plexuses and the microvessels of the leptomeninges.
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Bacteria can invade the meninges from the bloodstream through the choroid plexuses or directly through the microvessels of the leptomeninges and/or the brain parenchyma. In the case of crossing from parenchyma vessels, bacteria are drained to the subarachnoid space through the glymphatic pathway.
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Regardless of the site of crossing, meningeal invasion requires the crossing of two cellular barriers: an endothelial monolayer (in the choroid plexus or in the brain parenchyma and/or leptomeninges) followed by an epithelial monolayer (the choroid plexus ependyma, or the leptomeningeal monolayer of the pia mater or of a subarachnoid trabecula).
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A limited number of blood-borne bacteria can cross the blood–CNS barriers and cause meningitis. The extracellular pathogens that are involved are usually Neisseria meningitidis, Streptococcus pneumoniae or, in newborns, group B Streptococcus and Escherichia coli K1.
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Regardless of the mechanisms that are used to invade the meninges from the bloodstream, the level of bacteraemia plays a key part in meningeal tropism.
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The extracellular bacteria interact directly with the blood–CNS barriers.
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N. meningitidis is believed to cross the blood–CNS barriers by interacting with the leptomeninges and/or brain microvessels, and to open intercellular junctions following signals that are induced by the adhesion of bacteria to the endothelial cells.
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S. pneumoniae invades the meninges following interaction with the brain microvessels and is believed to transcytose through the endothelial cells following interactions with several host cell receptors.
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E. coli is believed to transcytose through endothelial cells, to have several attributes that enable it to adhere to endothelial cells and to induce signalling events that lead to bacterial invasion.
Abstract
The blood–brain barrier, which is one of the tightest barriers in the body, protects the brain from insults, such as infections. Indeed, only a few of the numerous blood-borne bacteria can cross the blood–brain barrier to cause meningitis. In this Review, we focus on invasive extracellular pathogens, such as Neisseria meningitidis, Streptococcus pneumoniae, group B Streptococcus and Escherichia coli, to review the obstacles that bacteria have to overcome in order to invade the meninges from the bloodstream, and the specific skills they have developed to bypass the blood–brain barrier. The medical importance of understanding how these barriers can be circumvented is underlined by the fact that we need to improve drug delivery into the brain.
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References
Thigpen, M. C. et al. Bacterial meningitis in the United States, 1998–2007. N. Engl. J. Med. 364, 2016–2025 (2011).
Kim, K. S. Human meningitis-associated Escherichia coli. EcoSal Plus http://dx.doi.org/10.1128/ecosalplus.ESP-0015-2015 (2016).
Maisey, H. C., Doran, K. S. & Nizet, V. Recent advances in understanding the molecular basis of group B Streptococcus virulence. Expert Rev. Mol. Med. 10, e27 (2008).
Tazi, A. et al. The surface protein HvgA mediates group B Streptococcus hypervirulence and meningeal tropism in neonates. J. Exp. Med. 207, 2313–2322 (2010).
Segura, M. et al. Latest developments on Streptococcus suis: an emerging zoonotic pathogen: part 1. Future Microbiol. 9, 441–444 (2014).
Be, N. A., Kim, K. S., Bishai, W. R. & Jain, S. K. Pathogenesis of central nervous system tuberculosis. Curr. Mol. Med. 9, 94–99 (2009).
Disson, O. & Lecuit, M. Targeting of the central nervous system by Listeria monocytogenes. Virulence 3, 213–221 (2012).
Banks, W. A. From blood–brain barrier to blood–brain interface: new opportunities for CNS drug delivery. Nat. Rev. Drug Discov. 15, 275–292 (2016).
Weller, R. O. Microscopic morphology and histology of the human meninges. Morphologie 89, 22–34 (2005). A manuscript that describes in detail the structures of the meningeal envelope.
Louveau, A., Harris, T. H. & Kipnis, J. Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 36, 569–577 (2015).
Brochner, C. B., Holst, C. B. & Mollgard, K. Outer brain barriers in rat and human development. Front. Neurosci. 9, 75 (2015).
Alcolado, R., Weller, R. O., Parrish, E. P. & Garrod, D. The cranial arachnoid and pia mater in man: anatomical and ultrastructural observations. Neuropathol. Appl. Neurobiol. 14, 1–17 (1988). A principle work on the histology and organization of the meninges.
Laman, J. D. & Weller, R. O. Drainage of cells and soluble antigen from the CNS to regional lymph nodes. J. Neuroimmune Pharmacol. 8, 840–856 (2013).
Strazielle, N. & Ghersi-Egea, J. F. Choroid plexus in the central nervous system: biology and physiopathology. J. Neuropathol. Exp. Neurol. 59, 561–574 (2000). A detailed explanation of the function and structure of the choroid plexus.
Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl Med. 4, 147ra111 (2012). A report that details the circulation of the liquid in the brain parenchyma and identifies the glymphatic pathway.
Abbott, N. J., Patabendige, A. A., Dolman, D. E., Yusof, S. R. & Begley, D. J. Structure and function of the blood–brain barrier. Neurobiol. Dis. 37, 13–25 (2010). A comprehensive review on the BBB.
Keaney, J. & Campbell, M. The dynamic blood–brain barrier. FEBS J. 282, 4067–4079 (2015).
Alvarez, J. I. et al. The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science 334, 1727–1731 (2011).
Bell, R. D. et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512–516 (2012).
Wosik, K. et al. Angiotensin II controls occludin function and is required for blood–brain barrier maintenance: relevance to multiple sclerosis. J. Neurosci. 27, 9032–9042 (2007).
Daneman, R., Zhou, L., Kebede, A. A. & Barres, B. A. Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468, 562–566 (2010).
Armulik, A. et al. Pericytes regulate the blood–brain barrier. Nature 468, 557–561 (2010).
Brinker, T., Stopa, E., Morrison, J. & Klinge, P. A new look at cerebrospinal fluid circulation. Fluids Barriers CNS 11, 16 (2014).
Redzic, Z. Molecular biology of the blood–brain and the blood–cerebrospinal fluid barriers: similarities and differences. Fluids Barriers CNS 8, 3 (2011). An investigation that underlines the structural and anatomical differences between the two main barriers that divide the blood and the brain.
Allt, G. & Lawrenson, J. G. Is the pial microvessel a good model for blood–brain barrier studies? Brain Res. Brain Res. Rev. 24, 67–76 (1997).
Rascher, G. & Wolburg, H. The tight junctions of the leptomeningeal blood–cerebrospinal fluid barrier during development. J. Hirnforsch. 38, 525–540 (1997). A paper that proposes that there is a functional barrier in the leptomeningeal vessels.
Dando, S. J. et al. Pathogens penetrating the central nervous system: infection pathways and the cellular and molecular mechanisms of invasion. Clin. Microbiol. Rev. 27, 691–726 (2014).
van Ginkel, F. W. et al. Pneumococcal carriage results in ganglioside-mediated olfactory tissue infection. Proc. Natl Acad. Sci. USA 100, 14363–14367 (2003).
Smith, A. L. et al. in Haemophilus Influenzae: Epidemiology, Immunology and Prevention of Disease (eds Sell, S. H. & Wright, P. F.) 89–109 (Elsevier Science, 1982).
Virji, M., Kayhty, H., Ferguson, D. J., Alexandrescu, C. & Moxon, E. R. Interactions of Haemophilus influenzae with cultured human endothelial cells. Microb. Pathog. 10, 231–245 (1991).
Virji, M., Kayhty, H., Ferguson, D. J., Alexandrescu, C. & Moxon, E. R. Interactions of Haemophilus influenzae with human endothelial cells in vitro. J. Infect. Dis. 165 (Suppl. 1), S115–S116 (1992).
Madsen, L. W., Svensmark, B., Elvestad, K., Aalbaek, B. & Jensen, H. E. Streptococcus suis serotype 2 infection in pigs: new diagnostic and pathogenetic aspects. J. Comp. Pathol. 126, 57–65 (2002).
Sanford, S. E. Gross and histopathological findings in unusual lesions caused by Streptococcus suis in pigs. II. Central nervous system lesions. Can. J. Vet. Res. 51, 486–489 (1987).
Williams, A. E. & Blakemore, W. F. Pathogenesis of meningitis caused by Streptococcus suis type 2. J. Infect. Dis. 162, 474–481 (1990).
Pron, B. et al. Interaction of Neisseria meningitidis with the components of the blood–brain barrier correlates with an increased expression of PilC. J. Infect. Dis. 176, 1285–1292 (1997).
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).
Iovino, F., Orihuela, C. J., Moorlag, H. E., Molema, G. & Bijlsma, J. J. Interactions between blood-borne Streptococcus pneumoniae and the blood–brain barrier preceding meningitis. PLoS ONE 8, e68408 (2013).
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).
Zelmer, A. et al. Differential expression of the polysialyl capsule during blood-to-brain transit of neuropathogenic Escherichia coli K1. Microbiology 154, 2522–2532 (2008).
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).
Dietzman, D. E., Fischer, G. W. & Schoenknecht, F. D. Neonatal Escherichia coli septicemia — bacterial counts in blood. J. Pediatr. 85, 128–130 (1974).
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).
Tenenbaum, T. et al. Polar bacterial invasion and translocation of Streptococcus suis across the blood–cerebrospinal fluid barrier in vitro. Cell. Microbiol. 11, 323–336 (2009).
Wong, H. R. Genetics and genomics in pediatric septic shock. Crit. Care Med. 40, 1618–1626 (2012).
Deghmane, A. E. et al. Emergence of new virulent Neisseria meningitidis serogroup C sequence type 11 isolates in France. J. Infect. Dis. 202, 247–250 (2010).
Read, R. C. Neisseria meningitidis; clones, carriage, and disease. Clin. Microbiol. Infect. 20, 391–395 (2014).
Harrison, O. B. et al. Epidemiological evidence for the role of the hemoglobin receptor, HmbR, in meningococcal virulence. J. Infect. Dis. 200, 94–98 (2009).
Bille, E. et al. Association of a bacteriophage with meningococcal disease in young adults. PLoS ONE 3, e3885 (2008).
Nassif, X. et al. Type-4 pili and meningococcal adhesiveness. Gene 192, 149–153 (1997).
Berry, J. L. & Pelicic, V. Exceptionally widespread nanomachines composed of type IV pilins: the prokaryotic Swiss Army knives. FEMS Microbiol. Rev. 39, 134–154 (2015).
Join-Lambert, O. et al. Meningococcal interaction to microvasculature triggers the tissular lesions of purpura fulminans. J. Infect. Dis. 208, 1590–1597 (2013).
Melican, K. & Dumenil, G. A humanized model of microvascular infection. Future Microbiol. 8, 567–569 (2013).
Bernard, S. C. et al. Pathogenic Neisseria meningitidis utilizes CD147 for vascular colonization. Nat. Med. 20, 725–731 (2014).
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).
Rudel, T., Scheurerpflug, I. & Meyer, T. F. Neisseria PilC protein identified as type-4 pilus tip-located adhesin. Nature 373, 357–359 (1995).
Morand, P. C., Tattevin, P., Eugene, E., Beretti, J. L. & Nassif, X. The adhesive property of the type IV pilus-associated component PilC1 of pathogenic Neisseria is supported by the conformational structure of the N-terminal part of the molecule. Mol. Microbiol. 40, 846–856 (2001).
Gray-Owen, S. D. Neisserial Opa proteins: impact on colonization, dissemination and immunity. Scand. J. Infect. Dis. 35, 614–618 (2003).
Virji, M., Makepeace, K., Ferguson, D. J., Achtman, M. & Moxon, E. R. Meningococcal Opa and Opc proteins: their role in colonization and invasion of human epithelial and endothelial cells. Mol. Microbiol. 10, 499–510 (1993).
Sa, E. C. C., Griffiths, N. J. & Virji, M. Neisseria meningitidis Opc invasin binds to the sulphated tyrosines of activated vitronectin to attach to and invade human brain endothelial cells. PLoS Pathog. 6, e1000911 (2010).
Comanducci, M. et al. NadA, a novel vaccine candidate of Neisseria meningitidis. J. Exp. Med. 195, 1445–1454 (2002).
Capecchi, B. et al. Neisseria meningitidis NadA is a new invasin which promotes bacterial adhesion to and penetration into human epithelial cells. Mol. Microbiol. 55, 687–698 (2005).
Nagele, V. et al. Neisseria meningitidis adhesin NadA targets β1 integrins: functional similarity to Yersinia invasin. J. Biol. Chem. 286, 20536–20546 (2011).
Scietti, L. et al. Exploring host–pathogen interactions through genome wide protein microarray analysis. Sci. Rep. 6, 27996 (2016).
Orihuela, C. J. et al. Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models. J. Clin. Invest. 119, 1638–1646 (2009).
Alqahtani, F. et al. Deciphering the complex three-way interaction between the non-integrin laminin receptor, galectin-3 and Neisseria meningitidis. Open Biol. 4, 140053 (2014).
Tunio, S. A. et al. The moonlighting protein fructose-1, 6-bisphosphate aldolase of Neisseria meningitidis: surface localization and role in host cell adhesion. Mol. Microbiol. 76, 605–615 (2010).
Merz, A. J., Enns, C. A. & So, M. Type IV pili of pathogenic Neisseriae elicit cortical plaque formation in epithelial cells. Mol. Microbiol. 32, 1316–1332 (1999).
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).
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).
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).
Soyer, M. et al. Early sequence of events triggered by the interaction of Neisseria meningitidis with endothelial cells. Cell. Microbiol. 16, 878–895 (2014).
Mikaty, G. et al. Extracellular bacterial pathogen induces host cell surface reorganization to resist shear stress. PLoS Pathog. 5, e1000314 (2009).
Coureuil, M. et al. Meningococcus hijacks a β2-adrenoceptor/β-arrestin pathway to cross brain microvasculature endothelium. Cell 143, 1149–1160 (2010).
Chamot-Rooke, J. et al. Posttranslational modification of pili upon cell contact triggers N. meningitidis dissemination. Science 331, 778–782 (2011).
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).
Linhartova, I. et al. Meningococcal adhesion suppresses proapoptotic gene expression and promotes expression of genes supporting early embryonic and cytoprotective signaling of human endothelial cells. FEMS Microbiol. Lett. 263, 109–118 (2006).
Schubert-Unkmeir, A., Sokolova, O., Panzner, U., Eigenthaler, M. & Frosch, M. Gene expression pattern in human brain endothelial cells in response to Neisseria meningitidis. Infect. Immun. 75, 899–914 (2007).
Jacobsen, M. C. et al. A critical role for ATF2 transcription factor in the regulation of E-selectin expression in response to non-endotoxin components of Neisseria meningitidis. Cell. Microbiol. 18, 66–79 (2016).
Coureuil, M. et al. Meningococcal type IV pili recruit the polarity complex to cross the brain endothelium. Science 325, 83–87 (2009).
Schubert-Unkmeir, A. et al. Neisseria meningitidis induces brain microvascular endothelial cell detachment from the matrix and cleavage of occludin: a role for MMP-8. PLoS Pathog. 6, e1000874 (2010).
Fisher, M. J. Brain regulation of thrombosis and hemostasis: from theory to practice. Stroke 44, 3275–3285 (2013).
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).
Dupin, N. et al. Chronic meningococcemia cutaneous lesions involve meningococcal perivascular invasion through the remodeling of endothelial barriers. Clin. Infect. Dis. 54, 1162–1165 (2012).
Muenzner, P. et al. Carcinoembryonic antigen family receptor specificity of Neisseria meningitidis Opa variants influences adherence to and invasion of proinflammatory cytokine-activated endothelial cells. Infect. Immun. 68, 3601–3607 (2000).
Slanina, H., Hebling, S., Hauck, C. R. & Schubert-Unkmeir, A. Cell invasion by Neisseria meningitidis requires a functional interplay between the focal adhesion kinase, Src and cortactin. PLoS ONE 7, e39613 (2012).
Simonis, A., Hebling, S., Gulbins, E., Schneider-Schaulies, S. & Schubert-Unkmeir, A. Differential activation of acid sphingomyelinase and ceramide release determines invasiveness of Neisseria meningitidis into brain endothelial cells. PLoS Pathog. 10, e1004160 (2014).
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).
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).
Ring, A., Weiser, J. N. & Tuomanen, E. I. Pneumococcal trafficking across the blood–brain barrier. Molecular analysis of a novel bidirectional pathway. J. Clin. Invest. 102, 347–360 (1998).
Iovino, F., Brouwer, M. C., van de Beek, D., Molema, G. & Bijlsma, J. J. Signalling or binding: the role of the platelet-activating factor receptor in invasive pneumococcal disease. Cell. Microbiol. 15, 870–881 (2013).
Iovino, F., Molema, G. & Bijlsma, J. J. Streptococcus pneumoniae interacts with pIgR expressed by the brain microvascular endothelium but does not co-localize with PAF receptor. PLoS ONE 9, e97914 (2014).
Zhang, J. R. et al. The polymeric immunoglobulin receptor translocates pneumococci across human nasopharyngeal epithelial cells. Cell 102, 827–837 (2000).
Iovino, F., Molema, G. & Bijlsma, J. J. Platelet endothelial cell adhesion molecule-1, a putative receptor for the adhesion of Streptococcus pneumoniae to the vascular endothelium of the blood–brain barrier. Infect. Immun. 82, 3555–3566 (2014).
Iovino, F., Seinen, J., Henriques-Normark, B. & van Dijl, J. M. How does Streptococcus pneumoniae invade the brain? Trends Microbiol. 24, 307–315 (2016).
Uchiyama, S. et al. The surface-anchored NanA protein promotes pneumococcal brain endothelial cell invasion. J. Exp. Med. 206, 1845–1852 (2009).
Mann, B. et al. Broadly protective protein-based pneumococcal vaccine composed of pneumolysin toxoid–CbpA peptide recombinant fusion protein. J. Infect. Dis. 209, 1116–1125 (2014).
Iovino, F. et al. Pneumococcal meningitis is promoted by single cocci expressing pilus adhesin RrgA. J. Clin. Invest. 126, 2821–2826 (2016).
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).
Banerjee, A. et al. Bacterial pili exploit integrin machinery to promote immune activation and efficient blood–brain barrier penetration. Nat. Commun. 2, 462 (2011).
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).
Seo, H. S., Mu, R., Kim, B. J., Doran, K. S. & Sullam, P. M. Binding of glycoprotein Srr1 of Streptococcus agalactiae to fibrinogen promotes attachment to brain endothelium and the development of meningitis. PLoS Pathog. 8, e1002947 (2012).
Mu, R. et al. Identification of a group B streptococcal fibronectin binding protein, SfbA, that contributes to invasion of brain endothelium and development of meningitis. Infect. Immun. 82, 2276–2286 (2014).
Chang, Y. C. et al. Glycosaminoglycan binding facilitates entry of a bacterial pathogen into central nervous systems. PLoS Pathog. 7, e1002082 (2011).
Nizet, V. et al. Invasion of brain microvascular endothelial cells by group B streptococci. Infect. Immun. 65, 5074–5081 (1997).
Cutting, A. S. et al. The role of autophagy during group B Streptococcus infection of blood–brain barrier endothelium. J. Biol. Chem. 289, 35711–35723 (2014).
Kim, B. J. et al. Bacterial induction of Snail1 contributes to blood–brain barrier disruption. J. Clin. Invest. 125, 2473–2483 (2015).
Logue, C. M. et al. Genotypic and phenotypic traits that distinguish neonatal meningitis-associated Escherichia coli from fecal E. coli isolates of healthy human hosts. Appl. Environ. Microbiol. 78, 5824–5830 (2012).
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).
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).
Krishnan, S., Fernandez, G. E., Sacks, D. B. & Prasadarao, N. V. IQGAP1 mediates the disruption of adherens junctions to promote Escherichia coli K1 invasion of brain endothelial cells. Cell. Microbiol. 14, 1415–1433 (2012).
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).
Kim, Y. V., Pearce, D. & Kim, K. S. Ca2+/calmodulin-dependent invasion of microvascular endothelial cells of human brain by Escherichia coli K1. Cell Tissue Res. 332, 427–433 (2008).
Parthasarathy, G., Yao, Y. & Kim, K. S. Flagella promote Escherichia coli K1 association with and invasion of human brain microvascular endothelial cells. Infect. Immun. 75, 2937–2945 (2007).
Prasadarao, N. V., Wass, C. A. & Kim, K. S. Endothelial cell GlcNAcβ1-4GlcNAc epitopes for outer membrane protein A enhance traversal of Escherichia coli across the blood–brain barrier. Infect. Immun. 64, 154–160 (1996).
Prasadarao, N. V. et al. Outer membrane protein A of Escherichia coli contributes to invasion of brain microvascular endothelial cells. Infect. Immun. 64, 146–153 (1996).
Teng, C. H. et al. NlpI contributes to Escherichia coli K1 strain RS218 interaction with human brain microvascular endothelial cells. Infect. Immun. 78, 3090–3096 (2010).
Badger, J. L., Wass, C. A. & Kim, K. S. Identification of Escherichia coli K1 genes contributing to human brain microvascular endothelial cell invasion by differential fluorescence induction. Mol. Microbiol. 36, 174–182 (2000).
Wang, M. H. & Kim, K. S. Cytotoxic necrotizing factor 1 contributes to Escherichia coli meningitis. Toxins (Basel) 5, 2270–2280 (2013).
Wang, X. et al. Sphingosine 1-phosphate activation of EGFR as a novel target for meningitic Escherichia coli penetration of the blood–brain barrier. PLoS Pathog. 12, e1005926 (2016).
Acknowledgements
The laboratory of X.N. is supported by the Fondation pour la Recherche Médicale, The French Agence Nationale de la Recherche, INSERM (French Institut National de la Santé et de la Recherche Médicale), CNRS (French Centre National de la Recherche Scientifique) and the University Paris Descartes, France.
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Glossary
- Tight junctions
-
Regions of neighbouring cells that are very closely associated, such that the cell membranes join together to form a barrier that is virtually impermeable to fluid. The major types of protein that are involved in these junctions are the claudins and occludin. These proteins associate with peripheral membrane proteins such as zona occludens 1 (ZO1), which are located on the intracellular side of the plasma membrane and which anchor the strands of membrane claudins and occludin to the actin cytoskeleton.
- Subarachnoid space
-
The anatomical space between the arachnoid mater and the pia mater. It is occupied by spongy tissue that consists of trabeculae (delicate, vascularized connective tissue filaments that extend from the arachnoid mater and blend into the pia mater) and intercommunicating channels in which the cerebrospinal fluid is contained.
- Venous sinuses
-
Venous channels that are located inside the dura mater of the brain. They can be conceptualized as trapped epidural veins. Unlike other veins in the body, they run along, rather than parallel to, arteries.
- Ventricular ependyma
-
The thin epithelial lining of the ventricular system of the brain. These cells are in continuity with the epithelium of the choroid plexuses.
- Transcytotic vesicles
-
Vesicles that transport bacteria or macromolecules across a cell, from the apical to the basolateral membrane.
- Glia limitans
-
A thin barrier that is formed of astrocyte endfeet and the associated parenchymal basal lamina that surrounds the brain and spinal cord. This barrier constitutes the outermost layer of neural tissue.
- Purpura fulminans
-
A syndrome that involves intravascular thrombosis and haemorrhagic infarction of the skin that is rapidly progressive, accompanied by vascular collapse and disseminated intravascular coagulation. Neisseria meningitidis infections are the main cause of infectious purpura fulminans.
- Exocytosis
-
The counterpart of endocytosis. In the context of this Review, exocytosis corresponds to active transport out of cells.
- G protein-coupled receptor
-
(GPCR). A member of a large family of receptors that sense molecules outside the cell and activate intracellular signal transduction pathways. Ligand binding causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor. The GPCR can then activate an associated G protein, the α-subunit of which affects intracellular signalling proteins or targets functional proteins.
- Adherens junctions
-
Protein complexes that occur at cell–cell junctions in epithelial and endothelial tissues and that are more basal than tight junctions. These junctions are formed by the association of cadherins.
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Coureuil, M., Lécuyer, H., Bourdoulous, S. et al. A journey into the brain: insight into how bacterial pathogens cross blood–brain barriers. Nat Rev Microbiol 15, 149–159 (2017). https://doi.org/10.1038/nrmicro.2016.178
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DOI: https://doi.org/10.1038/nrmicro.2016.178
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