Pathogenesis of bacterial meningitis: From bacteraemia to neuronal injury

Nature Reviews Neuroscience

Volumn 4, Issue 5, 2003, Pages 376-385

  Kim, Kwang Sik ^a  

^a JOHNS HOPKINS HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CASPASE; CD18 ANTIGEN; CHLOROTRIANISENE; CYTOKINE; ENDOTHELIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1BETA CONVERTING ENZYME; MATRIX METALLOPROTEINASE; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE; NITRIC OXIDE SYNTHASE; REACTIVE OXYGEN METABOLITE; TUMOR NECROSIS FACTOR ALPHA; BIOLOGICAL MARKER;

BACTEREMIA; BACTERIAL MENINGITIS; BACTERIAL TRANSLOCATION; BLOOD BRAIN BARRIER; ESCHERICHIA COLI; HAEMOPHILUS INFLUENZAE; HOST PATHOGEN INTERACTION; HUMAN; LISTERIA MONOCYTOGENES; MORBIDITY; MORTALITY; NERVE INJURY; NEUROTOXICITY; NONHUMAN; PATHOGENESIS; PLEOCYTOSIS; PRIORITY JOURNAL; REVIEW; STREPTOCOCCUS PNEUMONIAE; ANIMAL; BIOLOGICAL MODEL; CYTOLOGY; LEUKOCYTOSIS; MENINX; METABOLISM; MICROBIOLOGY; NERVE CELL; PATHOLOGY; VASCULAR ENDOTHELIUM;

BACTERIA (MICROORGANISMS); ESCHERICHIA COLI; HAEMOPHILUS; HAEMOPHILUS INFLUENZAE; LISTERIA; LISTERIA MONOCYTOGENES; STREPTOCOCCUS; STREPTOCOCCUS PNEUMONIAE;

ANIMALS; BACTEREMIA; BIOLOGICAL MARKERS; BLOOD-BRAIN BARRIER; ENDOTHELIUM, VASCULAR; ESCHERICHIA COLI; LEUKOCYTOSIS; MENINGES; MENINGITIS, BACTERIAL; MODELS, BIOLOGICAL; NEURONS;

EID: 0037868085     PISSN: 1471003X     EISSN: 14710048     Source Type: Journal    
DOI: 10.1038/nrn1103     Document Type: Article

References (103)

1. stcentury. IDSA Lecture Clin. Infect. Dis. 32, 675-685 (2001).
2. Dawson, K. G., Emerson, J. C. & Burns J. L. Fifteen years of experience with bacterial meningitis. Pediatr. Infec. Dis. J. 18, 816-822 (1999).
3. 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).
4. 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).
5. 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).
6. Tauber, M. G. & Moser, B. Cytokines and chemokines in meningeal inflammation: biology and clinical implications. Clin. Infect. Dis. 28, 1-12 (1999).
7. 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).
8. 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).
9. Braun, J. S. et al. Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nature Med. 5, 298-302 (1999).
10. 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).
11. Rubin, L. L. & Staddon, J. M. The cell biology of the blood-brain barrier. Annu. Rev. Neurosci. 22, 11-28 (1999).
12. Kim, K. S. Escherichia coli translocation of the blood-brain barrier. Infect. Immun. 69, 5217-5222 (2001).
13. 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).
14. Robbins, R. B. et al. Escherichia coli K1 capsular polysaccharide associated with neonatal meningitis. N. Engl. J. Med. 290, 1216-1220 (1974).
15. 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).
16. 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).
17. Sarff, L. D. et al. Epidemiology of Escherichia coli in healthy and diseased newborns. Lancet 1, 1099-1104 (1975).
18. 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).
19. Stins, M. F., Badger, J. L. & Kim, K S. Bacterial invasion and transcytosis in transfected human brain microvascular endothelial cells. Microb. Patfiog. 30, 19-28 (2001).
20. Dietzman, D. E., Fischer, G. W. & Schoenknecht, F. D. Neonatal Escherichia coli septicemia — bacterial counts in blood. J. Pediatr. 85, 128-130 (1974).
21. 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).
22. 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).
23. 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).
24. 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).
25. 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).
26. 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).
27. nd Gen. Meet. Aim. Soc. Microbiol. B216 (2002).
28. nd Gen. Meet Aim. Soc. Microbiol. B59 (2002).
29. Prasadarao, N. V., Wass, C. A. & Kim, K. S. Endothelial cell GlcNAcP-4GlcNAc epitopes for outer membrane protein A enhance traversal of Escherichia coli across the blood-brain barrier. Infect. Immun. 64, 154-160 (1996).
30. 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).
31. 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).
32. 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).
33. 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).
34. 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).
35. 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).
36. 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).
37. 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).
38. 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).
39. 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).
40. 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).
41. 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).
42. 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).
43. 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).
44. 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).
45. 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).
46. Nizet, V. et al. Invasion of brain microvascular endothelial cells by group B streptococci. Infect. Immun. 65, 5074-5081 (1997).
47. 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).
48. 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).
49. 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).
50. Mustafa, M. M. et al. Tumor necrosis factor in mediating experimental Haemophilus influenzae type B meningitis. J. Clin. Invest. 84, 1253-1259 (1989).
51. 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).
52. 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).
53. 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).
54. 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).
55. 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).
56. 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).
57. Lukes, S. A., Posner, J. B., Nielsen, S. & Armstrong, D. Bacterial infections of the CNS in neutropenic patients. Neurology 34, 269-275 (1984).
58. Bergstrom, T., Larson, H., Lincoln, K. & Winberg, J. Studies of urinary tract infection in infancy and childhood. J. Pediatr. 80, 858-866 (1972).
59. Syrogiannopoulos, G. A. et al. Sterile cerebrospinal fluid pleocytosis in young infants with urinary tract infection. Pediatr. Infect. Dis. J. 20, 927-930 (2001).
60. 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).
61. 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).
62. 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).
63. 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).
64. Koedel, U. et al. Lack of endothelial nitric oxide synthase aggravates murine pneumococcal meningitis. J. Neuropathol. Exp. Neurol. 11, 1041-1050 (2001).
65. Paul, R. et al. Matrix metalloproteinases contribute to the blood-brain barrier disruption during bacterial meningitis. Ann. Neurol. 44, 592-600 (1998).
66. 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).
67. Kieseier, B. C. et al. Differential expression of matrix metalloproteinases in bacterial meningitis. Brain 122, 1579-1587 (1999).
68. Koedel, U., Bayerlein, I., Paul, R., Sporer, B. & Pfister, H.-W. Pharmacologic interference with NF-kB activation attenuates central nervous system complications in experimental pneumococcal meningitis. J. Infect. Dis. 182, 1437-1445 (2000).
69. 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).
70. Lebel, M. H., et al. Dexamethasone therapy for bacterial meningitis. N. Engl. J. Med. 319, 964-971 (1988).
71. Ward, E. R. et al. Dexamethasone therapy for children with bacterial meningitis. Pediatr. 95, 21-28 (1995).
72. 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).
73. De Gans, J. & van de Beek, D. Dexamethasone in adults with bacterial meningitis. N. Engl. J. Med. 347, 1549-1615 (2002).
74. 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).
75. 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).
76. L-cysteine in pneumococcal meningitis in the rat. Neurosci. Lett. 225, 33-36 (1997).
77. Loeffler, J. M., Ringer, R., Hablutzel, M., Tauber, M. G. & Leib, S. L. The free radical scavenger a-phenyl-tert-butyl nitrone aggravates hippocampal apoptosis and learning deficits in experimental pneumococcal meningitis. J. Infect. Dis. 183, 247-252 (2001).
78. 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).
79. 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).
80. 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).
81. Ischiropoulos, H. et al. Peroxynitrite- mediated tyrosine nitration catalyzed by superoxide dismutase. Arch. Biochem. Biophys. 298, 431-437 (1992).
82. 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).
83. Szabo, C. Cell Death: The Role of PARP (CRC Press, Boca Raton, Florida, 2000).
84. 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).
85. 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).
86. 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).
87. McCracken, G. H. Jr, Mustafa, M. M., Ramilo, O., Olsen, K. D. & Risser, R. C. Cerebrospinal fluid interleukin 1P and tumor necrosis factor concentrations and outcome from neonatal Gram-negative enteric bacillary meningitis. Pediatr. Infect. Dis. J. 8, 155-159 (1989).
88. Mustafa, M. M. et al. Correlation of interleukin-1 P and cachectin concentrations in cerebrospinal fluid and outcome from bacterial meningitis. J. Pediatr. 115, 208-213 (1989).
89. Ichiyama, T., Hayashi, T., Nishikawa, M. & Furukawa, S. Levels of transforming growth factor P1, tumor necrosis factor a, and interleukin 6 in cerebrospinal fluid: association with clinical outcome for children with bacterial meningitis. Clin. Infect. Dis. 25, 328-329 (1997).
90. Leib, S. L. et al. Inhibition of matrix metalloproteinases and tumor necrosis factor-a converting enzyme as adjuvant therapy in pneumococcal meningitis. Brain 124, 734-1742 (2001).
91. 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).
92. Bogdan, I., Leib, S. L., Bergeron, M., Chow, L. & Tauber, M. G. Tumor necrosis factor a contributes to apoptosis in hippocampal neurons during experimental group B streptococcal meningitis. J. Infect Dis. 176, 693-697 (1997).
93. 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).
94. 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).
95. 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).
96. 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).
97. 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).
98. Pfister, L. A. et al. Endothelin inhibition improves cerebral blood flow and is neuroprotective in pneumococcal meningitis. Ann. Neurol. 47, 329-335 (2000).
99. 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).
100. 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).
101. L-cysteine in pneumococcal meningitis in the rat. Neurosci. Lett. 225, 33-36 (1997).
102. 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).
103. Lorenzl, S., et al. Protective effect of a 21-aminosteroid during experimental pneumococcal meningitis. J. Infect. Dis 172, 113-118 (1995).