Mechanisms of injury in bacterial meningitis
Abstract
PURPOSE OF REVIEW: This review describes the pathophysiology of cellular and axonal injury in bacterial meningitis. RECENT FINDINGS: Toll-like receptors have been recognized as important mediators for the initiation of the immune response within the central nervous system. Activation of microglial cells by bacterial products through these receptors increases their ability to phagocytose bacteria, but can also lead to destruction of neurons. The cholesterol-binding hemolysin pneumolysin has a direct toxic effect on neuronal cells. Adjuvant therapy with corticosteroids and glycerol improved the outcome of bacterial meningitis in clinical studies. SUMMARY: Brain damage in bacterial meningitis leading to long-term neurologic sequelae and death is caused by several mechanisms. Bacterial invasion and the release of bacterial compounds promote inflammation, invasion of leukocytes and stimulation of microglia. Leukocytes, macrophages and microglia release free radicals, proteases, cytokines and excitatory amino acids, finally leading to energy failure and cell death. Vasculitis, focal ischemia and brain edema subsequent to an increase in cerebrospinal fluid outflow resistance, breakdown of the blood-brain barrier and swelling of necrotic cells cause secondary brain damage.
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S. pneumoniae and N. meningitidis are both highly successful colonizers of the human nasopharynx.
“Streptococcus pneumoniae and N. meningitidis are both highly successful colonizers of the human nasopharynx.24”
From Community-acquired acute bacterial meningitis in adults: a clinical update (2019) · cites this paper as [24]
The recommended empirical regimen in the UK is a third-generation cephalosporin (ceftriaxone or cefotaxime), which has bactericidal activity for both S. pneumoniae and N. meningitidis, while achieving good CNS penetration.
“The recommended empirical regimen in the UK is a third-generation cephalosporin (ceftriaxone or cefotaxime), which has bactericidal activity for both S. pneumoniae and N. meningitidis, while achieving good CNS penetration.24”
From Community-acquired acute bacterial meningitis in adults: a clinical update (2019) · cites this paper as [24]
Cites
Dexamethasone in Adults with Bacterial Meningitis
de Gans, J., & van de Beek, D. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa021334 · Cited by 1,196 · see citing works
Rosenstein, N. E., Perkins, B. A., Stephens, D. S., Popović, T., & Hughes, J. M. (2001) · New England Journal of Medicine · doi:10.1056/nejm200105033441807 · Cited by 1,177 · see citing works
Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection
Malley, R., Henneke, P., Morse, S. C., Cieslewicz, M. J., Lipsitch, M., Thompson, C. M., Kurt‐Jones, E. A., Paton, J. C., Wessels, M. R., & Golenbock, D. T. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0435928100 · Cited by 704 · see citing works
ODIO, C. M., Faingezicht, I., Paris, M. M., Nassar, M., Baltodano, A., Rogers, J., Sáez‐Llorens, X., Olsen, K. D., & McCragken, G. H. (1991) · New England Journal of Medicine · doi:10.1056/nejm199105303242201 · Cited by 494 · see citing works
Bacterial DNA causes septic shock
Sparwasser, T. D., Miethke, T., Lipford, G. B., Borschert, K., Häcker, H., Heeg, K. M., & Wagner, H. (1997) · Nature · doi:10.1038/386336a0 · Cited by 405 · see citing works
Pathophysiology of Bacterial Meningitis: Mechanism(s) of Neuronal Injury
Scheld, W. M., Koedel, U., Nathan, B. R., & Pfister, H. (2002) · The Journal of Infectious Diseases · doi:10.1086/344939 · Cited by 325 · see citing works
Pneumococcal pneumolysin and H2O2 mediate brain cell apoptosis during meningitis
Braun, J., Sublett, J. E., Freyer, D., Mitchell, T. J., Cleveland, J. L., TUOMANEN, E. I., & Weber, J. R. (2002) · Journal of Clinical Investigation · doi:10.1172/jci12035 · Cited by 314 · see citing works
Orihuela, C. J., Mahdavi, J., Thornton, J., Mann, B., Wooldridge, K. G., Abouseada, N., Oldfield, N. J., Self, T., Ala’Aldeen, D. A. A., & Tuomanen, E. I. (2009) · Journal of Clinical Investigation · doi:10.1172/jci36759 · Cited by 303 · see citing works
Echchannaoui, H., Frei, K., Schnell, C., Leib, S. L., Zimmerli, W., & Landmann, R. M. (2002) · The Journal of Infectious Diseases · doi:10.1086/342845 · Cited by 303 · see citing works
Toll-like Receptors and Their Signaling Mechanisms
Akira, S., & Sato, S. (2003) · Scandinavian Journal of Infectious Diseases · doi:10.1080/00365540310015683 · Cited by 264 · see citing works
Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data
van de Beek, D., Farrar, J., de Gans, J., Hoang, N. T., MOLYNEUX, E. M., Peltola, H., Peto, T., Roine, I., Scarborough, M., Schultsz, C., et al. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70023-5 · Cited by 241 · see citing works
Leib, S. L. (2001) · Brain · doi:10.1093/brain/124.9.1734 · Cited by 228 · see citing works
Mini‐review Toll‐like receptors: networking for success
Underhill, D. M. (2003) · European Journal of Immunology · doi:10.1002/eji.200324037 · Cited by 226 · see citing works
Koedel, U., Angele, B., Rupprecht, T. A., Wagner, H., Roggenkamp, A., Pfister, H., & Kirschning, C. J. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.1.438 · Cited by 223 · see citing works
Apoptosis of Neurons in the Dentate Gyrus in Humans Suffering from Bacterial Meningitis
Nau, R., Soto, A., & Brück, W. (1999) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199903000-00006 · Cited by 203 · see citing works
Self-citationNeuronal injury mediated via stimulation of microglial toll-like receptor-9 (TLR9)
Iliev, A. I., Stringaris, A. K., Nau, R., & Neumann, H. (2004) · The FASEB Journal · doi:10.1096/fj.03-0670fje · Cited by 192 · see citing works
Self-citationThe surface-anchored NanA protein promotes pneumococcal brain endothelial cell invasion
Uchiyama, S., Carlin, A. F., Khosravi, A., Weiman, S., Banerjee, A., Quach, D., Hightower, G. K., Mitchell, T. J., Doran, K. S., & Nizet, V. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem.20090386 · Cited by 184 · see citing works
Peltola, H., Roine, I., Fernández, J., Zavala, I., Ayala, S. G., Mata, A. G., Arbo, A., Bologna, R., Miño, G., Goyo, J., et al. (2007) · Clinical Infectious Diseases · doi:10.1086/522534 · Cited by 183 · see citing works
Cognitive Impairment in Adults with Good Recovery after Bacterial Meningitis
van de Beek, D., Schmand, B. A., de Gans, J., Weisfelt, M., Vaessen, H., Dankert, J., & Vermeulen, M. (2002) · The Journal of Infectious Diseases · doi:10.1086/344229 · Cited by 183 · see citing works
PavA of Streptococcus pneumoniae Modulates Adherence, Invasion, and Meningeal Inflammation
Pracht, D., Elm, C., Gerber, J., Bergmann, S., Rohde, M., Seiler, M., Kim, K., Jenkinson, H. F., Nau, R., & Hammerschmidt, S. (2005) · Infection and Immunity · doi:10.1128/iai.73.5.2680-2689.2005 · Cited by 175 · see citing works
Self-citationZysk, G., Schneider-Wald, B. K., Hwang, J. H., et al. (2001) · Infection and Immunity · doi:10.1128/iai.69.2.845-852.2001 · Cited by 174 · see citing works
Akira, S., & Hoshino, K. (2003) · The Journal of Infectious Diseases · doi:10.1086/374749 · Cited by 165 · see citing works
MyD88 is required for mounting a robust host immune response to Streptococcus pneumoniae in the CNS
Koedel, U., Rupprecht, T. A., Angele, B., Heesemann, J., Wagner, H., Pfister, H., & Kirschning, C. J. (2004) · Brain · doi:10.1093/brain/awh171 · Cited by 156 · see citing works
Neuropsychological sequelae of bacterial and viral meningitis
Schmidt, H., Heimann, B., Djukic, M., Mazurek, C., Fels, C., Wallesch, C.-W., & Nau, R. (2006) · Brain · doi:10.1093/brain/awh711 · Cited by 155 · see citing works
Self-citationRibes, S., Ebert, S., Regen, T., Agarwal, A., Tauber, S. C., Czesnik, D., Spreer, A., Bunkowski, S., Eiffert, H., Hanisch, U., et al. (2009) · Infection and Immunity · doi:10.1128/iai.01110-09 · Cited by 144 · see citing works
Self-citationvan Sorge, N. M., Quach, D., Gurney, M. A., Sullam, P. M., Nizet, V., & Doran, K. S. (2009) · The Journal of Infectious Diseases · doi:10.1086/598217 · Cited by 132 · see citing works
Klein, M., Obermaier, B., Angele, B., Pfister, H., Wagner, H., Koedel, U., & Kirschning, C. J. (2008) · The Journal of Infectious Diseases · doi:10.1086/591626 · Cited by 130 · see citing works
Pneumolysin Causes Neuronal Cell Death through Mitochondrial Damage
Braun, J., Hoffmann, O. M., Schickhaus, M., Freyer, D., Dagand, E., Bermpohl, D., Mitchell, T. J., Bechmann, I., & Weber, J. R. (2007) · Infection and Immunity · doi:10.1128/iai.00031-07 · Cited by 126 · see citing works
Matrix Metalloproteinase–9 in Pneumococcal Meningitis: Activation via an Oxidative Pathway
Meli, D. N., Christen, S., & Leib, S. L. (2003) · The Journal of Infectious Diseases · doi:10.1086/374644 · Cited by 115 · see citing works
Stringaris, A. K., Geisenhainer, J., Bergmann, F., Balshüsemann, C., Lee, U., Zysk, G., Mitchell, T. J., Keller, B. U., Kuhnt, U., Gerber, J., et al. (2002) · Neurobiology of Disease · doi:10.1006/nbdi.2002.0561 · Cited by 113 · see citing works
Self-citationEbert, S., Gerber, J., Bader, S., Mühlhauser, F., Brechtel, K., Mitchell, T., & Nau, R. (2005) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2004.10.005 · Cited by 110 · see citing works
Self-citationPneumolysin Localizes to the Cell Wall of Streptococcus pneumoniae
Price, K. E., & Camilli, A. (2009) · Journal of Bacteriology · doi:10.1128/jb.01489-08 · Cited by 107 · see citing works
Loeffler, J. M., Ringer, R., Hablützel, M., et al. (2001) · The Journal of Infectious Diseases · doi:10.1086/317921 · Cited by 101 · see citing works
Rifampin Reduces Early Mortality in ExperimentalStreptococcus pneumoniaeMeningitis
Nau, R., Wellmer, A., Soto, A., Koch, K., Schneider, O., Schmidt, H., Gerber, J., Michel, U., & Brück, W. (1999) · The Journal of Infectious Diseases · doi:10.1086/314760 · Cited by 99 · see citing works
Self-citationEffects of Clinically Used Antioxidants in Experimental Pneumococcal Meningitis
Auer, M., Pfister, L., Leppert, D., Täuber, M. G., & Leib, S. L. (2000) · The Journal of Infectious Diseases · doi:10.1086/315658 · Cited by 93 · see citing works
Tenenbaum, T., Papandreou, T., Gellrich, D., Friedrichs, U., Seibt, A., Adam, R., Friedrich, C., Galla, H., Schwerk, C., & Schroten, H. (2008) · Cellular Microbiology · doi:10.1111/j.1462-5822.2008.01255.x · Cited by 92 · see citing works
Kim, Y. S., & Täuber, M. G. (1996) · Infection and Immunity · doi:10.1128/iai.64.8.3148-3153.1996 · Cited by 87 · see citing works
Lipoproteins in Staphylococcus aureus Mediate Inflammation by TLR2 and Iron-Dependent Growth In Vivo
Schmaler, M., Nyffenegger, N., Ferracin, F., Landolt, L. Z., Biswas, L., Götz, F., & Landmann, R. M. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0804292 · Cited by 85 · see citing works
Virulence factors and the pathogenesis of disease causedby
Mitchell, T. J. (2000) · Research in Microbiology · doi:10.1016/s0923-2508(00)00175-3 · Cited by 79 · see citing works
Meningitis‐associated hearing loss: Protection by adjunctive antioxidant therapy
Klein, M., Koedel, U., Pfister, H., & Kastenbauer, S. (2003) · Annals of Neurology · doi:10.1002/ana.10684 · Cited by 76 · see citing works
TRAIL limits excessive host immune responses in bacterial meningitis
Hoffmann, O. M., Priller, J., Prozorovski, T., Schulze‐Topphoff, U., Baeva, N., Lünemann, J. D., Aktaş, O., Mahrhofer, C., Stricker, S., Zipp, F., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30356 · Cited by 73 · see citing works
Meli, D. N., Loeffler, J. M., Baumann, P., Neumann, U., Buhl, T., Leppert, D., & Leib, S. L. (2004) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2004.01.026 · Cited by 67 · see citing works
Bifrare, Y., Gianinazzi, C., Imboden, H., et al. (2003) · Hippocampus · doi:10.1002/hipo.10142 · Cited by 67 · see citing works
Mildner, A., Djukic, M., Garbe, D., Wellmer, A., Kuziel, W. A., Mack, M., Nau, R., & Prinz, M. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.4.2713 · Cited by 66 · see citing works
Self-citationBöttcher, T., von Mering, M., Ebert, S., et al. (2003) · Neuroscience Letters · doi:10.1016/s0304-3940(03)00404-x · Cited by 65 · see citing works
Grandgirard, D., Oberson, K., Bühlmann, A., Ackermann‐Gäumann, R., & Leib, S. L. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00812-09 · Cited by 62 · see citing works
Axonal injury, a neglected cause of CNS damage in bacterial meningitis
Nau, R., Gerber, J., Bunkowski, S., & Brück, W. (2004) · Neurology · doi:10.1212/01.wnl.0000106826.82670.30 · Cited by 52 · see citing works
Self-citationNoske, N., Kämmerer, U., Rohde, M., & Hammerschmidt, S. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0804383 · Cited by 48 · see citing works
Spreer, A., Lugert, R., Stoltefaut, V., Hoecht, A., Eiffert, H., & Nau, R. (2009) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181a036c0 · Cited by 45 · see citing works
Self-citationStrain-dependent disruption of blood–cerebrospinal fluid barrier byStreptoccocus suisin vitro
Tenenbaum, T., Adam, R. ⁄. D., Eggelnpöhler, I., Matalon, D., Seibt, A., Novotny, G. E. K., Galla, H., & Schroten, H. (2005) · FEMS Immunology & Medical Microbiology · doi:10.1016/j.femsim.2004.12.006 · Cited by 45 · see citing works
Short- and long-term changes in gene expression mediated by the activation of TLR9
Klaschik, S., Tross, D., Shirota, H., & Klinman, D. M. (2009) · Molecular Immunology · doi:10.1016/j.molimm.2009.11.014 · Cited by 45 · see citing works
Increased neuronal proliferation in human bacterial meningitis
Gerber, J., Tauber, S. C., Armbrecht, I., Schmidt, H., Brück, W., & Nau, R. (2009) · Neurology · doi:10.1212/wnl.0b013e3181b9c892 · Cited by 42 · see citing works
Self-citationTauber, S. C., Ebert, S., Weishaupt, J. H., Reich, A., Nau, R., & Gerber, J. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181b7fde5 · Cited by 40 · see citing works
Self-citationSinghi, S. C., Järvinen, A., & Peltola, H. (2008) · The Pediatric Infectious Disease Journal · doi:10.1097/inf.0b013e318175d177 · Cited by 40 · see citing works
Bogaert, D., Thompson, C. M., Trzciński, K., Malley, R., & Lipsitch, M. (2009) · Vaccine · doi:10.1016/j.vaccine.2009.10.085 · Cited by 38 · see citing works
Schmidt, H. (2001) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(00)00402-1 · Cited by 35 · see citing works
Iliev, A. I., Djannatian, J. R., Opazo, F., Gerber, J., Nau, R., Mitchell, T. J., & Wouters, F. S. (2008) · Molecular Microbiology · doi:10.1111/j.1365-2958.2008.06538.x · Cited by 35 · see citing works
Self-citationHsieh, H., Wang, H.-H., Wu, C., Tung, W., & Yang, C. (2009) · Neurotoxicity Research · doi:10.1007/s12640-009-9111-4 · Cited by 29 · see citing works
Expression of Death‐related Proteins in Dentate Granule Cells in Human Bacterial Meningitis
Gerber, J., Brück, W., Stadelmann, C., et al. (2001) · Brain Pathology · doi:10.1111/j.1750-3639.2001.tb00410.x · Cited by 28 · see citing works
Self-citationKanoh, Y., Ohara, T., Kanoh, M., et al. (2008) · Inflammation · doi:10.1007/s10753-007-9054-y · Cited by 27 · see citing works
Letièmbre, M., Echchannaoui, H., Ferracin, F., Rivest, S., & Landmann, R. M. (2005) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2005.06.016 · Cited by 27 · see citing works
Melatonin Is Neuroprotective in ExperimentalStreptococcus pneumoniaeMeningitis
Gerber, J., Lotz, M., Ebert, S., et al. (2005) · The Journal of Infectious Diseases · doi:10.1086/427816 · Cited by 27 · see citing works
Self-citationEvidence for frequent focal and diffuse acute axonal injury in human bacterial meningitis
Gerber, J., Seitz, R., Bunkowski, S., et al. (2009) · Clinical Neuropathology · doi:10.5414/npp28033 · Cited by 24 · see citing works
Self-citationEchchannaoui, H., Leib, S. L., Neumann, U., et al. (2007) · BMC Infectious Diseases · doi:10.1186/1471-2334-7-25 · Cited by 23 · see citing works
Gianinazzi, C., Grandgirard, D., Simon, F., et al. (2004) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/63.6.610 · Cited by 21 · see citing works
Spreer, A., Gerber, J., Baake, D., Hanssen, M., Huether, G., & Nau, R. (2006) · Journal of Neuroscience Research · doi:10.1002/jnr.21055 · Cited by 21 · see citing works
Self-citationInducible Nitric Oxide Synthase Mediates Hippocampal Caspase-3 Activation in Pneumococcal Meningitis
Braun, J. (2009) · International Journal of Neuroscience · doi:10.1080/00207450802479970 · Cited by 12 · see citing works
Simvastatin attenuates leukocyte recruitment in experimental bacterial meningitis
Winkler, F., Angele, B., Pfister, H., & Koedel, U. (2009) · International Immunopharmacology · doi:10.1016/j.intimp.2008.11.019 · Cited by 11 · see citing works
Sellner, J., Grandgirard, D., Gianinazzi, C., et al. (2008) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2008.10.004 · Cited by 9 · see citing works
Nau, R., & Gerber, J. (2003) · e-Neuroforum · doi:10.1515/nf-2003-0102 · Cited by 2 · see citing works
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Mook-Kanamori, B. B., Geldhoff, M., van der Poll, T., & van de Beek, D. (2011) · Clinical Microbiology Reviews · doi:10.1128/cmr.00008-11 · Cited by 492 · see citing works
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- Authors
- Gerber, J., & Nau, R.
- Affiliations
- Universitätsklinikum Aachen (DE)
- Evangelisches Krankenhaus Göttingen-Weende (DE)
- Corresponding author
- Gerber, Joachim
- ORCID
- Nau, Roland
- Venue
- Current Opinion in Neurology
- Published
- 2010-06
- Volume
- 23
- Issue
- 3
- Pages
- 312-318
- ISSN
- 1350-7540 (ISSN-L)
- OpenAlex
- W1997358669
- Cited by
- 149
- References
- 70
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 15 · 2023: 6 · 2022: 3 · 2021: 7 · 2020: 7 · 2019: 10 · 2018: 7 · 2017: 6 · 2016: 10 · 2015: 10 · 2014: 14 · 2013: 19 · 2012: 13
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Opinion in Neurology (publishedVersion)
- PubMed (publishedVersion)
- GRO (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- bacterial meningitis, pathophysiology, axonal injury, neuronal injury, Toll-like receptors, microglial activation, pneumolysin, neuroinflammation, free radicals, excitatory amino acids, corticosteroids, vasculitis, focal cerebral ischemia, cerebral edema, blood-brain barrier disruption, neurological sequelae
- MeSH terms
- Adrenal Cortex Hormones, Animals, Bacterial Proteins, Brain, Brain Edema, Chemotaxis, Leukocyte, Humans, Nerve Degeneration, Streptolysins, Meningitis, Bacterial, Microglia, Inflammation Mediators, Toll-Like Receptors
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