Pneumolysin is the Main Inducer of Cytotoxicity to Brain Microvascular Endothelial Cells Caused by Streptococcus Pneumoniae

Overview

Journal Infect Immun

Publisher American Society for Microbiology

Specialty Allergy & Immunology

Date 2001 Feb 13

PMID 11159977

Citations 62

Authors

G Zysk

J H Hwang

L Bejo

K S Kim

T J Mitchell

R Hakenbeck

H P Heinz

Affiliations

Soon will be listed here.

Abstract

In pneumococcal meningitis it is assumed that bacteria cross the blood-brain barrier (BBB), which consists mainly of cerebral endothelial cells. The effect of Streptococcus pneumoniae on the BBB was investigated with an in vitro BBB model using a human brain microvascular endothelial cell line (HBMEC) and primary cultures of bovine brain microvascular endothelial cells (BBMEC). Within a few hours of incubation with pneumococci, rounding and detachment of the HBMEC were observed, and the transendothelial electrical resistance of the BBMEC monolayer decreased markedly. An S. pneumoniae mutant deficient in pneumolysin did not affect the integrity of the endothelial cell monolayer. Neither cell wall fragments nor isolated pneumococcal cell walls induced changes of endothelial cell morphology. However, purified pneumolysin caused endothelial cell damage comparable to that caused by the viable pneumococci. The cell detachment was dependent on de novo protein synthesis and required the activities of caspase and tyrosine kinases. The results show that pneumolysin is an important component for damaging the BBB and may contribute to the entry of pneumococci into the cerebral compartment and to the development of brain edema in pneumococcal meningitis.

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References

Gilbert R, Rossjohn J, Parker M, Tweten R, Morgan P, Mitchell T . Self-interaction of pneumolysin, the pore-forming protein toxin of Streptococcus pneumoniae. J Mol Biol. 1998; 284(4):1223-37. DOI: 10.1006/jmbi.1998.2258. View

Nau R, Soto A, Bruck W . Apoptosis of neurons in the dentate gyrus in humans suffering from bacterial meningitis. J Neuropathol Exp Neurol. 1999; 58(3):265-74. DOI: 10.1097/00005072-199903000-00006. View

Winter A, Comis S, Osborne M, Tarlow M, Stephen J, Andrew P . A role for pneumolysin but not neuraminidase in the hearing loss and cochlear damage induced by experimental pneumococcal meningitis in guinea pigs. Infect Immun. 1997; 65(11):4411-8. PMC: 175634. DOI: 10.1128/iai.65.11.4411-4418.1997. View

Bowman P, Ennis S, Rarey K, Betz A, GOLDSTEIN G . Brain microvessel endothelial cells in tissue culture: a model for study of blood-brain barrier permeability. Ann Neurol. 1983; 14(4):396-402. DOI: 10.1002/ana.410140403. View

Tiraby J, Fox M . Marker discrimination in transformation and mutation of pneumococcus. Proc Natl Acad Sci U S A. 1973; 70(12):3541-5. PMC: 427276. DOI: 10.1073/pnas.70.12.3541. View

Houldsworth S, Andrew P, Mitchell T . Pneumolysin stimulates production of tumor necrosis factor alpha and interleukin-1 beta by human mononuclear phagocytes. Infect Immun. 1994; 62(4):1501-3. PMC: 186313. DOI: 10.1128/iai.62.4.1501-1503.1994. View

AVERY O, Macleod C, McCarty M . STUDIES ON THE CHEMICAL NATURE OF THE SUBSTANCE INDUCING TRANSFORMATION OF PNEUMOCOCCAL TYPES : INDUCTION OF TRANSFORMATION BY A DESOXYRIBONUCLEIC ACID FRACTION ISOLATED FROM PNEUMOCOCCUS TYPE III. J Exp Med. 2009; 79(2):137-58. PMC: 2135445. DOI: 10.1084/jem.79.2.137. View

Pfister H, Feiden W, Einhaupl K . Spectrum of complications during bacterial meningitis in adults. Results of a prospective clinical study. Arch Neurol. 1993; 50(6):575-81. DOI: 10.1001/archneur.1993.00540060015010. View

Pfister H, Fontana A, Tauber M, Tomasz A, Scheld W . Mechanisms of brain injury in bacterial meningitis: workshop summary. Clin Infect Dis. 1994; 19(3):463-79. DOI: 10.1093/clinids/19.3.463. View

10.

Ring A, Weiser J, Tuomanen E . Pneumococcal trafficking across the blood-brain barrier. Molecular analysis of a novel bidirectional pathway. J Clin Invest. 1998; 102(2):347-60. PMC: 508893. DOI: 10.1172/JCI2406. View

11.

Leib S, Kim Y, Chow L, Sheldon R, Tauber M . 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. 1996; 98(11):2632-9. PMC: 507723. DOI: 10.1172/JCI119084. View

12.

Stins M, Gilles F, Kim K . Selective expression of adhesion molecules on human brain microvascular endothelial cells. J Neuroimmunol. 1997; 76(1-2):81-90. DOI: 10.1016/s0165-5728(97)00036-2. View

13.

Rubins J, Janoff E . Pneumolysin: a multifunctional pneumococcal virulence factor. J Lab Clin Med. 1998; 131(1):21-7. DOI: 10.1016/s0022-2143(98)90073-7. View

14.

Duane P, Rubins J, Weisel H, Janoff E . Identification of hydrogen peroxide as a Streptococcus pneumoniae toxin for rat alveolar epithelial cells. Infect Immun. 1993; 61(10):4392-7. PMC: 281171. DOI: 10.1128/iai.61.10.4392-4397.1993. View

15.

Chen J, Morrison D . Construction and properties of a new insertion vector, pJDC9, that is protected by transcriptional terminators and useful for cloning of DNA from Streptococcus pneumoniae. Gene. 1988; 64(1):155-64. DOI: 10.1016/0378-1119(88)90489-1. View

16.

Neuhaus J, Risau W, Wolburg H . Induction of blood-brain barrier characteristics in bovine brain endothelial cells by rat astroglial cells in transfilter coculture. Ann N Y Acad Sci. 1991; 633:578-80. DOI: 10.1111/j.1749-6632.1991.tb15667.x. View

17.

Rossjohn J, Gilbert R, Crane D, Morgan P, Mitchell T, ROWE A . The molecular mechanism of pneumolysin, a virulence factor from Streptococcus pneumoniae. J Mol Biol. 1998; 284(2):449-61. DOI: 10.1006/jmbi.1998.2167. View

18.

Schuchat A, Robinson K, Wenger J, Harrison L, Farley M, Reingold A . Bacterial meningitis in the United States in 1995. Active Surveillance Team. N Engl J Med. 1998; 337(14):970-6. DOI: 10.1056/NEJM199710023371404. View

19.

Geelen S, Bhattacharyya C, Tuomanen E . The cell wall mediates pneumococcal attachment to and cytopathology in human endothelial cells. Infect Immun. 1993; 61(4):1538-43. PMC: 281397. DOI: 10.1128/iai.61.4.1538-1543.1993. View

20.

Heumann D, Barras C, SEVERIN A, Glauser M, Tomasz A . Gram-positive cell walls stimulate synthesis of tumor necrosis factor alpha and interleukin-6 by human monocytes. Infect Immun. 1994; 62(7):2715-21. PMC: 302873. DOI: 10.1128/iai.62.7.2715-2721.1994. View