Key Points
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The sequence of events that are responsible for the onset of bacterial meningitis has been charted, particularly in the case of Escherichia coli. In general terms, it involves bacterial invasion of the meninges, increased permeability of the blood–brain barrier and pleocytosis, and neuronal injury. The molecular mechanisms that underlie these events remain poorly understood.
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Bacterial invasion of the meninges requires a high level of bacteraemia. In addition, several bacterial and host molecules that are crucial for invasion have been identified. It has also been established that successful invasion depends on pathogen traversal as live bacteria. To this end, bacteria induce the reorganization of the host-cell cytoskeleton so that they are engulfed and protected from lysosomal activities. The relevant signalling pathways have begun to be mapped.
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Once bacteria reach the cerebrospinal fluid, their proliferation leads to the increased permeability of the blood–brain barrier through the release of proinflammatory and toxic compounds, the nature of which has been elucidated in some cases.
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A consequence of the increased permeability and pleocytosis is that neuronal injury takes place in response to increased intracranial pressure, oedema and toxicity. Several molecules have been proposed to elicit cell death, and targeting them constitutes a potential therapeutic strategy against the neurological sequelae that accompany meningitis.
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The elucidation of the molecular pathways that participate in the bacterial infection of the meninges has provided us with new targets to develop preventive and therapeutic strategies. Future studies should continue characterizing these molecular events, and should establish whether other pathogenic bacteria follow similar rules.
Abstract
Bacterial meningitis is an important cause of mortality and morbidity despite advances in antimicrobial therapy. A key factor that contributes to the high prevalence of this condition is the incomplete understanding of its pathogenesis. Most cases of bacterial meningitis develop as a result of haematogenous spread, but it is unclear how circulating bacteria cross the blood–brain barrier, and how bacterial entry into the central nervous system results in inflammation and in complications such as pleocytosis, blood–brain barrier disruption and neuronal injury. Recent studies have shed light on the pathogenic mechanisms of bacterial translocation across the blood–brain barrier and the meningitis-associated complications. I propose that bacterial translocation, a key step for the development of meningitis, is the result of specific bacteria–host interactions, and that its complications are the result of multiple host responses to the invading microorganism.
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References
Fauci, A. S. Infectious diseases: considerations for the 21st century. IDSA Lecture Clin. Infect. Dis. 32, 675–685 (2001).
Dawson, K. G., Emerson, J. C. & Burns J. L. Fifteen years of experience with bacterial meningitis. Pediatr. Infec. Dis. J. 18, 816–822 (1999).
Grimwood, K., Anderson, P., Anderson V., Tan, L. & Nolan, T. Twelve-year outcomes following bacterial meningitis: further evidence for persisting effects. Arch. Dis. Child. 83, 111–116 (2000).
Pfister, H. -W., Fontana, A., Tauber, M. G. Tomasz, A. & Scheld, W. M. Mechanisms of brain injury in bacterial meningitis: workshop summary. Clin. Infect. Dis. 19, 463–479 (1994).
Van Furth, A. M., Roord, J. J. & Van Furth, R. Roles of proinflammatory and anti-inflammatory cytokines in pathology of bacterial meningitis and effect of adjunctive therapy. Infect. Immun. 64, 4883–4890 (1996).
Tauber, M. G. & Moser, B. Cytokines and chemokines in meningeal inflammation: biology and clinical implications. Clin. Infect. Dis. 28, 1–12 (1999).
Scheld, W. M., Koedel, U., Nathan, B. & Pfister, H. -W. Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury. J. Infect. Dis. Suppl. 186, S225–233 (2002). A comprehensive review on neuronal injury in bacterial meningitis.
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).
Braun, J. S. et al. Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nature Med. 5, 298–302 (1999).
Nau, R., Soto, A. & Bruck, W. Apoptosis of neurons in the dentate gyrus in humans suffering from bacterial meningitis. J. Neuropath. Exp. Neurol. 58, 265–274 (1999).
Rubin, L. L. & Staddon, J. M. The cell biology of the blood–brain barrier. Annu. Rev. Neurosci. 22, 11–28 (1999).
Kim, K. S. Escherichia coli translocation of the blood–brain barrier. Infect. Immun. 69, 5217–5222 (2001). A review on bacterial translocation of the blood–brain barrier.
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).
Robbins, R. B. et al. Escherichia coli K1 capsular polysaccharide associated with neonatal meningitis. N. Engl. J. Med. 290, 1216–1220 (1974).
Gross, R. J., Ward, L. R., Threlfall, E. J., Cheasty, T. & Rowe, B. Drug resistance among Escherichia coli strains isolated from cerebrospinal fluid. J. Hyg. 90, 195–198 (1982).
Korhonen, T. K. et al. Serotypes hemolysin production and receptor recognition of Escherichia coli strains associated with neonatal sepsis and meningitis. Infect. Immun. 488, 486–491 (1985).
Sarff, L. D. et al. Epidemiology of Escherichia coli in healthy and diseased newborns. Lancet 1, 1099–1104 (1975).
Kim, K. S., Wass, C. A. & Cross, A. S. Blood–brain barrier permeability during the development of experimental bacterial meningitis in the rat. Exp. Neurol. 45, 253–257 (1997).
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).
Dietzman, D. E., Fischer, G. W. & Schoenknecht, F. D. Neonatal Escherichia coli septicemia — bacterial counts in blood. J. Pediatr. 85, 128–130 (1974).
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).
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).
Moxon, E. R. & Ostrow, P. T. Haemophilus influenzae meningitis in infant rats: role of bacteremia in pathogenesis of age-dependent inflammatory responses in cerebrospinal fluid. J. Infect. Dis. 135, 303–307 (1977).
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).
Petersdorf, R. G., Swarner, D. R. & Garcia, M. Studies on the pathogenesis of meningitis II. Development of meningitis during pneumococcal bacteremia. J. Clin. Invest. 41, 320–327 (1962).
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).
Khan, N. A. et al. Gp96 is a receptor for OmpA in human brain microvascular endothelial cells. Abstr. 102nd Gen. Meet. Am. Soc. Microbiol. B216 (2002).
Khan, N. A., Elliott, S. J. & Kim, K. S. Role of FimH in Escherichia coli interactions with human brain microvascular endothelial cells. Abstr. 102nd Gen. Meet. Am. Soc. Microbiol. B59 (2002).
Prasadarao, N. V., Wass, C. A. & Kim, K. S. Endothelial cell GlcNAcβ-4GlcNAc epitopes for outer membrane protein A enhance traversal of Escherichia coli across the blood–brain barrier. Infect. Immun. 64, 154–160 (1996).
Parkkinen, J., Korhonen, T. K., Pere, A., Hacker, J. & Soiinilla, S. Binding sites of the rat brain for Escherichia coli S-fimbriae associated with neonatal meningitis. J. Clin. Invest. 81, 860–865 (1988).
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).
Prasadarao, N. V., Wass, C. A., Hacker, J., Jann, K. & Kim, K. S. Adhesion of S-fimbriated Escherichia coli to brain glycolipids mediated by sfaA gene-encoded protein of S-fimbriae. J. Biol. Chem. 268, 10356–10363 (1993).
Huang, S. H. et al. Escherichia coli invasion of brain microvascular endothelia cell in vitro and in vivo: molecular cloning and characterization of invasion gene ibe10. Infect. Immun. 63, 4470–4475 (1995).
Huang, S. H. et al. Identification and characterization of an Escherichia coli invasion gene locus, ibeB, required for penetration of brain microvascular endothelia cells. Infect. Immun. 67, 2103–2109 (1999).
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).
Badger, J., Wass, C., Weissman, S. & Kim, K. S. Application of signature-tagged mutagenesis for the identification of Escherichia coli K1 genes that contribute to invasion of the blood–brain barrier. Infect. Immun. 68, 5056–5061 (2000).
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). The first study to show the contributions of CNF1 and RhoA activation to E. coli K1 invasion of the CNS.
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).
Prasadarao, N. V., Wass, C. A., Huang, S. -H. & Kim, K. S. Identification and characterization of a novel Ibe 10 binding protein that contributes to Escherichia coli invasion of brain microvascular endothelial cells. Infect. Immun. 67, 1131–1138 (1999).
Chung, J. W. et al. 37kDa lamina receptor precursor modulates cytotoxic necrotizing factor 1-mediated RhoA activation and bacterial uptake. J. Biol. Chem. (in the press). This paper shows the identification of 37LRP as the receptor for CNF1.
Prasadarao, N. A., Wass, C. A., Stins, M. F., 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).
Reddy, M. A., Wass, C. A., Kim, K. S., Schlaepfer, D. D. & Prasadarao, N. V. Involvement of focal adhesion kinases in Escherichia coli invasion of human microvascular endothelial cells. Infect. Immun. 68, 6419–6422 (2000).
Reddy, M. A., Prasadarao, N. 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). This paper shows that activations of FAK and PI3K are required for E. coli K1 invasion of human brain microvascular endothelial cells.
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).
Greiffenberg, L. et al. 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).
Nizet, V. et al. Invasion of brain microvascular endothelial cells by group B streptococci. Infect. Immun. 65, 5074–5081 (1997).
Hoffman, J. A., Wass, C., Stins, M. F. & Kim, K. S. The capsule supports survival but not traversal of Escherichia coli K1 across the blood–brain barrier. Infect. Immun. 67, 3566–3570 (1999).
Kim, K. J., Elliott, S. A., DiCello, F., Stins, M. F. & Kim K. S. The K1 capsule modulates trafficking of Escherichia coli-containing vacuoles and enhances intracellular bacterial survival in human brain microvascular endothelial cells. Cell. Microbiol. (in the press). This paper shows a new phenotype associated with the K1 capsule in E. coli movement in human brain microvascular endothelial cells.
Saukkonen, K. et al. The role of cytokines in the generation of inflammation and tissue damage in experimental gram-positive meningitis. J. Exp. Med. 171, 439–448 (1990).
Mustafa, M. M. et al. Tumor necrosis factor in mediating experimental Haemophilus influenzae type B meningitis. J. Clin. Invest. 84, 1253–1259 (1989).
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).
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, 342–349 (1995).
Munoz, F. M., Hawkins, E. P., Bullard, D. C., Beaudet, 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).
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).
Lesse, A. J., Moxon, E. R., Zwahlen, A. & Scheld, 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).
Fishbein, D. B., Palmer, D. L., Porter, K. M. & Reed, W. P. Bacterial meningitis in the absence of CSF pleocytosis. Arch. Intern. Med. 141, 1369–1372 (1981).
Lukes, S. A., Posner, J. B., Nielsen, S. & Armstrong, D. Bacterial infections of the CNS in neutropenic patients. Neurology 34, 269–275 (1984).
Bergstrom, T., Larson, H., Lincoln, K. & Winberg, J. Studies of urinary tract infection in infancy and childhood. J. Pediatr. 80, 858–866 (1972).
Syrogiannopoulos, G. A. et al. Sterile cerebrospinal fluid pleocytosis in young infants with urinary tract infection. Pediatr. Infect. Dis. J. 20, 927–930 (2001).
Laflamme, N. & Rivest, S. Toll-like receptor 4: the missing link of the central innate immune response triggered by circulating gram-negative bacterial cell wall components. FASEB J. 15, 155–63 (2001).
Kastenbauer, S., Koedel, U., Becker, B. F. & Pfister, H. -W. Pneumococcal meningitis in the rat: evaluation of peroxynitrite scavengers for adjunctive therapy. Eur. J. Pharmacol. 449, 177–181 (2002).
Koedel, U., Winkler, F., Angele, B., Fontana, A. & Pfister, H. -W. Meningitis-associated central nervous system complications are mediated by the activation of poly(ADP-ribose) polymerase. J. Cereb. Blood Flow Metab. 22, 39–49 (2002).
Winkler, F., Koedel, U., Kastenbauer, S. & Pfister, H. -W. Differential expression of nitric oxide syntheses in bacterial meningitis: role of the inducible isoform for blood–brain barrier breakdown. J. Infect. Dis. 183, 1749–1759 (2001).
Koedel, U. et al. Lack of endothelial nitric oxide synthase aggravates murine pneumococcal meningitis. J. Neuropathol. Exp. Neurol. 11, 1041–50 (2001).
Paul, R. et al. Matrix metalloproteinases contribute to the blood–brain barrier disruption during bacterial meningitis. Ann. Neurol. 44, 592–600 (1998).
Leppert, D., Leib, S. L., Grygar, C. & Miller, K. M. Matrix metalloproteinases (MMP)-8 and MMP-9 in cerebrospinal fluid during bacterial meningitis: association with blood–brain barrier damage and neurological sequelae. Clin. Infect. Dis. 31, 80–84 (2000).
Kieseier, B. C. et al. Differential expression of matrix metalloproteinases in bacterial meningitis. Brain 122, 1579–1587 (1999).
Koedel, U., Bayerlein, I., Paul, R., Sporer, B. & Pfister, H. -W. Pharmacologic interference with NF-κB activation attenuates central nervous system complications in experimental pneumococcal meningitis. J. Infect. Dis. 182, 1437–1445 (2000).
Koedel, U. et al. Role of caspase-1 in experimental pneumococcal meningitis: evidence from pharmacologic caspase inhibition and caspase-1-deficient mice. Ann. Neurol. 51, 319–329 (2001).
Lebel, M. H., et al. Dexamethasone therapy for bacterial meningitis. N. Engl. J. Med. 319, 964–971 (1988). This paper shows the beneficial effect of dexamethosone therapy in reducing hearing deficits in children with H. influenzae type b meningitis.
Ward, E. R. et al. Dexamethasone therapy for children with bacterial meningitis. Pediatr. 95, 21–28 (1995).
Zysk, G. et al. Anti-inflammatory treatment influences neuronal apoptotic cell death in the dentate gyrus in experimental pneumococcal meningitis. J. Neuropathol. Exp. Neurol. 55, 722–728 (1996).
De Gans, J. & van de Beek, D. Dexamethasone in adults with bacterial meningitis. N. Engl. J. Med. 347, 1549–1615 (2002).
Leib, S. L., Kim, Y. S., Chow, L. L., Sheldon, R. A. & Tauber, M. G. Reactive oxygen intermediates contribute to necrotic and apoptotic neuronal injury in an infant rat model of bacterial meningitis due to group B streptococci. J. Clin. Invest. 98, 2632–2639 (1996). Highlights the role of reactive oxygen species in neuronal injury associated with experimental group B streptococcal meningitis.
Auer, M., Pfister, L. A., Leppert, D., Tauber, M. G. & Leib, S. L. Effects of clinically used antioxidants in experimental pneumococcal meningitis. J. Infect. Dis. 182, 347–350 (2000).
Koedel, U. & Pfister, H. W. Protective effect of the antioxidant N-acetyl-L-cysteine in pneumococcal meningitis in the rat. Neurosci. Lett. 225, 33–36 (1997).
Loeffler, J. M., Ringer, R., Hablutzel, M., Tauber, M. G. & Leib, S. L. The free radical scavenger α-phenyl-tert-butyl nitrone aggravates hippocampal apoptosis and learning deficits in experimental pneumococcal meningitis. J. Infect. Dis. 183, 247–252 (2001).
Koedel, U. et al. Experimental pneumococcal meningitis: cerebrovascular alterations, brain edema, and meningeal inflammation linked to the production of nitric oxide. Ann. Neurol. 37, 313–323 (1995).
Leib, S. L., Kim, Y. S., Black, S. M., Tureen, J. H. & Tauber, M. G. Inducible nitric oxide synthase and the effect of aminoguanidine in experimental neonatal meningitis. J. Infect. Dis. 177, 692–700 (1998).
Radi, R., Beckman, J. S., Bush, K. M. & Freeman, B. A. Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Arch. Biochem. Biophys. 288, 481–487 (1991).
Ischiropoulos, H. et al. Peroxynitrite- mediated tyrosine nitration catalyzed by superoxide dismutase. Arch. Biochem. Biophys. 298, 431–437 (1992).
Bolanos, J. P., Heales, S. J., Land, J. M. & Clark, J. B. Effect of peroxynitrite on the mitochondrial respiratory chain: differential susceptibility of neurons and astrocytes in primary culture. J. Neurochem. 64, 1965–1972 (1995).
Szabo, C. Cell Death: The Role of PARP (CRC Press, Boca Raton, Florida, 2000).
McCracken, G. H. Jr, Sarff, L. D., Glode, M. P. & Mize, S. G. Relation between Escherichia coli K1 capsular polysaccharide antigen and clinical outcome in neonatal meningitis. Lancet 2, 246–250 (1974).
Mertsola, J., et al. Endotoxin concentrations in cerebrospinal fluid correlate with clinical severity and neurologic outcome of Haemophilus influenzae type B meningitis. Am. J. Dis. Child. 145, 1099–1103 (1991).
Schneider, O., Michel, U., Zysk, G., Dubuis, O. & Nau, R. Clinical outcome in pneumococcal meningitis correlates with CSF lipoteichoic acid concentrations. Neurology 53, 1584–1587 (1999).
McCracken, G. H. Jr, Mustafa, M. M., Ramilo, O., Olsen, K. D. & Risser, R. C. Cerebrospinal fluid interleukin 1β and tumor necrosis factor concentrations and outcome from neonatal Gram-negative enteric bacillary meningitis. Pediatr. Infect. Dis. J. 8, 155–159 (1989).
Mustafa, M. M. et al. Correlation of interleukin-1β and cachectin concentrations in cerebrospinal fluid and outcome from bacterial meningitis. J. Pediatr. 115, 208–213 (1989).
Ichiyama, T., Hayashi, T., Nishikawa, M. & Furukawa, S. Levels of transforming growth factor β1, tumor necrosis factor α, and interleukin 6 in cerebrospinal fluid: association with clinical outcome for children with bacterial meningitis. Clin. Infect. Dis. 25, 328–329 (1997).
Leib, S. L. et al. Inhibition of matrix metalloproteinases and tumor necrosis factor-α converting enzyme as adjuvant therapy in pneumococcal meningitis. Brain 124, 734–1742 (2001). This study highlights the roles of MMPs and TNFα converting enzyme in neuronal injury associated with experimental pneumococcal meningitis.
Leib, S. L., Leppert, D., Clements, J. & Tauber, M. G. Matrix metalloproteinases contribute to brain damage in experimental pneumococcal meningitis. Infect. Immun. 68, 615–620 (2000).
Bogdan, I., Leib, S. L., Bergeron, M., Chow, L. & Tauber, M. G. Tumor necrosis factor α contributes to apoptosis in hippocampal neurons during experimental group B streptococcal meningitis. J. Infect. Dis. 176, 693–697 (1997).
Spranger, M., Schwab, S., Krempien, S., Winterholler, M. & Steiner, T. Excess glutamate levels in the cerebrospinal fluid predict clinical outcome of bacterial meningitis. Arch. Neurol. 53, 992–996 (1996).
Perry, V. L., Young, R. S. K., Aquila, W. J. & During, M. J. Effect of experimental Escherichia coli meningitis on concentrations of excitatory and inhibitory amino acids in the rabbit brain: in vivo microdialysis study. Pediatr. Res. 34, 187–198 (1993).
Leib, S. L., Kim, Y. S., Ferriero, D. M. & Tauber, M. G. Neuroprotective effect of excitatory amino acid antagonist kynurenic acid in experimental bacterial meningitis. J. Infect. Dis. 173, 166–171 (1996). This study shows the role of excitatory amino acids in neuronal injury associated with experimental group B streptococcal meningitis.
Tumani, H. et al. Inhibition of glutamine synthetase in rabbit pneumococcal meningitis is associated with neuronal apoptosis in the dentate gyrus. Glia 30, 11–18 (2000).
Koedel, U., Gorriz, C., Lorenzl, S. & Pfister, H. -W. Increased endothelin levels in cerebrospinal fluid samples from adults with bacterial meningitis. Clin. Infect. Dis. 25, 329–330 (1997).
Pfister, L. A. et al. Endothelin inhibition improves cerebral blood flow and is neuroprotective in pneumococcal meningitis. Ann. Neurol. 47, 329–335 (2000).
Hoffman, J. A., Badger, J. L., Zhang, Y., Huang, S. H. & Kim, K. S. Escherichia coli K1 aslA contributes to invasion of brain microvascular endothelial cells in vitro and in vivo. Infect. Immun. 68, 5062–5067 (2000).
Ostergaard, C. et al. Inhibition of leukocyte entry into the brain by the selectin blocker fucoidin decreases interleukin-1 (IL-1) levels but increases IL-8 levels in cerebrospinal fluid during experimental pneumococcal meningitis in rabbits. Infect. Immun. 68, 3153–3157 (2000).
Koedel, U. & Pfister, H. -W. Protective effect of the antioxidant N-acetyl-L-cysteine in pneumococcal meningitis in the rat. Neurosci. Lett. 225, 33–36 (1997).
Kastenbauer, S., Koedel, U., & Pfister, H. -W. Role of peroxynitrite as a mediator of pathophysiological alterations in experimental pneumococcal meningitis. J. Infect. Dis. 180, 1164–1170 (1999).
Lorenzl, S., et al. Protective effect of a 21-aminosteroid during experimental pneumococcal meningitis. J. Infect. Dis 172, 113–118 (1995).
Acknowledgements
This work was supported by NIH grants. I thank K. J. Kim for his help with figures.
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Glossary
- MORBIDITY
-
The incidence or prevalence of a disease in a population.
- PLEOCYTOSIS
-
The presence of a greater than normal number of cells in the cerebrospinal fluid.
- TIGHT JUNCTION
-
A belt-like region of adhesion between adjacent epithelial or endothelial cells. Tight junctions regulate paracellular flux, and contribute to the maintenance of cell polarity by stopping molecules from diffusing within the plane of the membrane.
- PINOCYTOSIS
-
The cellular uptake of extracellular fluid. It involves the formation of caveolae by the cell membrane, which pinch off to form vesicles known as pinosomes in the cytoplasm.
- CHOROID PLEXUS
-
A site of production of cerebrospinal fluid in the adult brain. It is formed by the invagination of ependymal cells into the ventricles, which become richly vascularized.
- QUORUM SENSING
-
A mechanism used by many bacterial pathogens to detect bacterial cell numbers in host tissues. Cell densities are indicated by the concentration of autoinducers, which regulate the expression of specific genes.
- ISOGENIC
-
A strain in which the chromosomes of different bacteria are identical.
- S FIMBRIAE
-
Glycoprotein-binding structures of the membrane of Escherichia coli, which participates in bacterial binding to endothelial cells during the development of meningitis.
- TRANSPOSON
-
Mobile DNA elements that can relocate within the genome of their hosts. Transposons can be used for various applications, including insertional mutagenesis, gene identification, gene tagging and DNA sequencing.
- SIGNATURE-TAGGED TRANSPOSON MUTAGENESIS
-
A technique for detecting genes that are required for survival and growth in vivo that uses modified transposons to allow high-throughput screening of randomly generated mutants.
- TRANS
-
Indicates a trans-acting element. A regulatory genetic element whose effects are independent of its position and, therefore, can be located in a different DNA molecule to the gene being regulated.
- YEAST TWO-HYBRID SYSTEM
-
System used to determine the existence of direct interactions between proteins. It involves the use of plasmids that encode two hybrid proteins; one of them is fused to the GAL4 DNA-binding domain and the other one is fused to the GAL4 activation domain. The two proteins are expressed together in yeast and, if they interact, the resulting complex drives the expression of a reporter gene, commonly β-galactosidase.
- DOMINANT-NEGATIVE
-
A mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.
- CASPASES
-
A family of intracellular cysteine endopeptidases that have a key role in inflammation and mammalian apoptosis. They cleave proteins at specific aspartate residues.
- INTRACISTERNAL
-
Administered directly into the cerebral ventricles.
- LEUKOPENIA
-
A reduction in the number of white blood cells below 5000 mm−3.
- CIRCUMVENTRICULAR ORGANS
-
Brain regions that have a rich vascular plexus with a specialized arrangement of the blood vessels. The junctions between the capillary endothelial cells are not tight in the blood vessels of these regions, allowing the diffusion of large molecules. These organs include the organum vasculosum of the lamina terminalis, the subfornical organ, the median eminence and the area postrema. Although not classed as circumventricular organs, the choroid plexus and leptomeninges are also highly vascularized and are rapidly activated by circulating pathogens.
- CD14
-
The first lipopolysaccharide receptor to be characterized. It exists two forms: membrane CD14 (mCD14) and soluble CD14 (sCD14). mCD14 is present at the surface of myeloid cells and acts as a glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein, whereas sCD14 lacks the GPI anchor, but can bind lipopolysaccharide to activate cells that are devoid of mCD14, such as endothelial cells.
- TOLL-LIKE RECEPTORS
-
A large family of receptors that are expressed at the surface of leukocytes and microglial cells. They are responsible for engaging the innate immune system in response to pathogens.
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Kim, K. Pathogenesis of bacterial meningitis: from bacteraemia to neuronal injury. Nat Rev Neurosci 4, 376–385 (2003). https://doi.org/10.1038/nrn1103
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DOI: https://doi.org/10.1038/nrn1103
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