Transcytosis and Signalling of Pneumococci at the Blood Brain Barrier

  • Joerg R. Weber
  • Elaine I. Tuomanen


Meningeal pathogens, including pneumococci, meningococci and Haemophilus influenzae,attach to and colonize nasopharyngeal cells, invade to cause bacteremia and, in the presence of sustained high level bacteremia, they cross cerebral microvessels to enter the subarachnoid space and cause meningitis. A common feature for all three pathogens is the two step invasive process. First, adherence is enabled by multiple ligand receptor interactions usually between host cell glycoconjugates and bacterial proteins. Following adherence, a second step actively upregulates a new ligand receptor pair required to penetrate the human cell. At the level of the blood brain barrier, each bacteria has solved this paradigm in a different manner. In vitro the process requires several hours and bacteria strictly regulate the composition of their surfaces so as to direct trafficking of their “passenger” vacuole across the cell.


Blood Brain Barrier Bacterial Meningitis Streptococcus Pneumoniae Pneumococcal Meningitis Secretory Component 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Braun, J., Novak, R., Bodmer, S., Cleveland, J., Tuomanen, E., 1999, Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nature Med. 5: 298–302.PubMedCrossRefGoogle Scholar
  2. Braun, J., Novak, R., Murray, P., Eischen, C., Susin, S., Kroemer, G., Halle, A., Weber, J., Tuomanen, E., Cleveland, J., 2000, Apoptosis inducing factor mediates microglial and neuronal apoptosis caused by pneumococcus. Submitted.Google Scholar
  3. Bohr, V., Paulson, OP., Rasmussen, N., 1984, Late.neurologic sequelae and features of prognostic impact. Arch. Neurol. 41: 1045–1049.PubMedCrossRefGoogle Scholar
  4. Braun, J., Sublett, J., Freyer, D., Mitchell, T., Cleveland, J., Tuomanen, E., Weber, J., 2000, Pneumococcal pneumolysin and hydrogen peroxide mediate brain cell apoptosis during meningitis. Submitted.Google Scholar
  5. Campbell G., Silberman R., 1998, Drug-Resistant Streptococcus pneumoniae. Clin. Infect. Dis. 26: 1188–1195.PubMedCrossRefGoogle Scholar
  6. Charpentier, E., Novak, R., Tuomanen, E., 2000, ClpC is involved in regulation of growth inhibition at high temperature, autolysis, transformation and virulence in Streptococcus pneumoniae. Molec. Micro. 37: 717–726.CrossRefGoogle Scholar
  7. Cundell, D., Gerard, N., Gerard, C., Idanpaan-Heikkila, I., Tuomanen, E., 1995, Streptococcus pneumoniae anchors to activated eukaryotic cells by the receptor for platelet activating factor. Nature 377: 435–438.PubMedCrossRefGoogle Scholar
  8. Freyer, D., Manz, R., Ziegenhorn, A., Weih, M., Angstwurm, K., Docke, W.D., Meisel, A., Schumann, R.R., Schonfelder, G., Dirnagl, U., Weber, J.R., 1999, Cerebral endothelial cells release TNFa after stimulation with cell walls of Streptococcus pneumoniae and regulate iNOS and ICAM-1 expression via autocrine loops. J. Immunol. 163: 4308–4314.PubMedGoogle Scholar
  9. Freyer, D., Weih, M., Weber, J.R., 1996, Pneumococcal cell wall components induce nitric oxide synthase and TNF-alpha in astroglial-enriched cultures. Glia 16: 1–6.PubMedCrossRefGoogle Scholar
  10. Garcia, J., Sanchez-Beato, R., Medrano, F, Lopez, R., 1998, Versatility of chline-binding domain. Microb. Drug Res. 4: 25–36.CrossRefGoogle Scholar
  11. Gosink, K., Mann, E., Guglielmo, C., Tuomanen, E., Masure, HR. 2000. Role of novel choline binding proteins in virulence of Streptococcus pneumoniae. Infect. Immun. 68: 5690–5695.PubMedCrossRefGoogle Scholar
  12. Hammerschmidt, S., Talay, S, Brandtzaeg, P., Chhatwal, G., 1997, SpsA, a novel pneumococcal surface protein with specific binding to secretory immunoglobulin A and secretory component. Molec. Microbiol. 25: 1113–1124.CrossRefGoogle Scholar
  13. Koedel, U., Pfister, HW., 1999, Superoxide production by primary rat cerebral endothelial cells in response to pneumococci. J. Neuroimmunol. 96: 190–200.PubMedCrossRefGoogle Scholar
  14. Nesin, M., Ramirez, M., Tomasz, A., 1998, Capsular transformation of a multidrug-resistant Streptococcus pneumoniae in vivo. J. Infect. Dis. 177: 707–713.PubMedCrossRefGoogle Scholar
  15. Novak, R., Charpentier, E., Braun, J., Park, E., Murti, S., Tuomanen, E., Masure, H.R., 2000, Extracellular targetting of choline binding proteins in Streptococcus pneumoniae by a zinc metalloprotease. Molec. Microbiol. 36: 366–376.CrossRefGoogle Scholar
  16. Park, E., Novak, R., Penfound, T., Masure, H.R., Mitchell, T., Tuomanen, E., 2000, Regulation of expression of cbpA, a major pneumococcal adhesin. Submitted.Google Scholar
  17. Prinz, M., Kann, O., Draheim, H.J., Schumann, R.R., Kettenmann, H., Weber, J.R., Hanisch, U.K., 1999, Microglial activation by components of gram-positive and-negative bacteria: distinct and common routes to the induction of ion channels and cytokines. J. Neuropathol. Exp. Neurol. 58: 1078–1089.PubMedCrossRefGoogle Scholar
  18. Ring, A., Weiser, J., Tuomanen, E., 1998, Pneumococcal trafficking across the blood brain barrier. J. Clin. Invest. 102: 1–14.CrossRefGoogle Scholar
  19. Rosenow, C., Ryan, P., Weiser, J., Johnson, S., Fontan, P., Ortqvist, A., Masure, H.R., 1997, Contribution of a novel choline binding protein to adherence, colonization, and immunogenicity of Streptococcus pneumoniae. Molec. Microbiol. 25: 819–829.CrossRefGoogle Scholar
  20. Schuchat, A., Robinson, K., Wenger, J., Harrison, L., Farley, M., Reingold, A., Lefkowitz, L., Perkins, B., 1997, Bacterial meningitis in the United States. N. Engl. J. Med. 337: 970–976.PubMedCrossRefGoogle Scholar
  21. Schumann, R., Pfeil, D., Freyer, D., Buerger, W., Lamping, N., Kirschning, C.J., Goebel, U.B., Weber, J.R., 1998, Lipopolysaccharide and pneumococcal cell wall components activate the mitogen activated protein kinases (MAPK) erk-1, erk-2, and p38 in astrocytes. Glia 22: 295–305.PubMedCrossRefGoogle Scholar
  22. Thornsberry, C., Ogilvie, P., Kahn, J., Mauriz, Y., 1997, Surveillance of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States in 1996-1997 respiratory season. Diag. Microb. Infect. Dis. 29: 249–257.CrossRefGoogle Scholar
  23. Yoshimura, A., Lien, E., Ingalls, R.R., Tuomanen, E., Dziarski, R., Golenbock, D., 1999, Cutting edge: recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2. J. Immunol. 163: 1–5.PubMedGoogle Scholar
  24. Weber, J., Angstwurm, K., Burger, W., Einhaupl, K.M., Dirnagl, U., 1995, Anti-ICAM-1 (CD54) monoclonal antibody reduces inflammatory changes in experimental bacterial meningitis. J. Neuroimmunol. 63: 63–68.PubMedCrossRefGoogle Scholar
  25. Weiser, J., Austrian, R. Sreenivasan, P, Masure, H.R., 1994, Phase variation in pneumococcal opacity: relationship between colonial morphology and nasopharyngeal colonization. Infect. Immun. 62: 2582–2589.PubMedGoogle Scholar
  26. Zhang, J-R., Mostov, K., Lamm, M., Nanno, M., Shimida, S., Ohwaki, M., Tuomanen, E., 2000, The polymeric immunoglobulin receptor translocates pneumococci across the human nasopharyngeal epithelial cells. Cell 102: 827–837.PubMedCrossRefGoogle Scholar
  27. Zysk, G., Bruck, W., Gerber, J., Brück, Y., Prange, H.W., Nau, R., 1996, Anti-inflammatory treatment influences neuronal apoptosis in the dentate gyrus in experimental pneumococcal meningitis. J. Neuropath. Exp. Neurol. 55: 722–728.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Joerg R. Weber
    • 1
  • Elaine I. Tuomanen
    • 2
  1. 1.Dept of NeurologyUniversitaetsklinikum Charit 9BerlinGermany
  2. 2.Dept of Infectious DiseasesSt. Jude Children’s Research HospitalMemphisUSA

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