Skip to main content
Top
Published in: BMC Infectious Diseases 1/2010

Open Access 01-12-2010 | Research article

Bacteremia causes hippocampal apoptosis in experimental pneumococcal meningitis

Authors: Christian Østergaard, Stephen L Leib, Ian Rowland, Christian T Brandt

Published in: BMC Infectious Diseases | Issue 1/2010

Login to get access

Abstract

Background

Bacteremia and systemic complications both play important roles in brain pathophysiological alterations and the outcome of pneumococcal meningitis. Their individual contributions to the development of brain damage, however, still remain to be defined.

Methods

Using an adult rat pneumococcal meningitis model, the impact of bacteremia accompanying meningitis on the development of hippocampal injury was studied. The study comprised of the three groups: I. Meningitis (n = 11), II. meningitis with attenuated bacteremia resulting from iv injection of serotype-specific pneumococcal antibodies (n = 14), and III. uninfected controls (n = 6).

Results

Pneumococcal meningitis resulted in a significantly higher apoptosis score 0.22 (0.18-0.35) compared to uninfected controls (0.02 (0.00-0.02), Mann Whitney test, P = 0.0003). Also, meningitis with an attenuation of bacteremia by antibody treatment resulted in significantly reduced apoptosis (0.08 (0.02-0.20), P = 0.01) as compared to meningitis.

Conclusions

Our results demonstrate that bacteremia accompanying meningitis plays an important role in the development of hippocampal injury in pneumococcal meningitis.
Appendix
Available only for authorised users
Literature
1.
go back to reference Østergaard C, Konradsen HB, Samuelsson S: Clinical presentation and prognostic factors of Streptococcus pneumoniae meningitis according the focus of infection. BMC Infect Dis. 2005, 5: 1-11. 10.1186/1471-2334-5-93.CrossRef Østergaard C, Konradsen HB, Samuelsson S: Clinical presentation and prognostic factors of Streptococcus pneumoniae meningitis according the focus of infection. BMC Infect Dis. 2005, 5: 1-11. 10.1186/1471-2334-5-93.CrossRef
2.
go back to reference Weisfelt M, Beek van de D, Spanjaard L, Reitsma JB, de Gans J: Clinical features, complications, and outcome in adults with pneumococcal meningitis: a prospective case series. Lancet Neurol. 2006, 5: 123-9. 10.1016/S1474-4422(05)70288-X.CrossRefPubMed Weisfelt M, Beek van de D, Spanjaard L, Reitsma JB, de Gans J: Clinical features, complications, and outcome in adults with pneumococcal meningitis: a prospective case series. Lancet Neurol. 2006, 5: 123-9. 10.1016/S1474-4422(05)70288-X.CrossRefPubMed
3.
go back to reference Brandt CT, Frimodt-Møller N, Lundgren JD, Pedersen M, Skovsted IC, Rowland IJ, Østergaard C: Evaluation of anti-pneumococcal capsular antibodies as adjunctive therapy in experimental pneumococcal meningitis. J Antimicrob Chemother. 2006, 58: 1291-4. 10.1093/jac/dkl401.CrossRefPubMed Brandt CT, Frimodt-Møller N, Lundgren JD, Pedersen M, Skovsted IC, Rowland IJ, Østergaard C: Evaluation of anti-pneumococcal capsular antibodies as adjunctive therapy in experimental pneumococcal meningitis. J Antimicrob Chemother. 2006, 58: 1291-4. 10.1093/jac/dkl401.CrossRefPubMed
4.
go back to reference Østergaard C, O'Reilly T, Brandt C, Frimodt-Møller N, Lundgren JD: The influence of the blood bacterial load on the meningeal inflammatory response in Streptococcus pneumoniae meningitis. BMC Infect Dis. 2006, 6: 1-7. 10.1186/1471-2334-6-1.CrossRef Østergaard C, O'Reilly T, Brandt C, Frimodt-Møller N, Lundgren JD: The influence of the blood bacterial load on the meningeal inflammatory response in Streptococcus pneumoniae meningitis. BMC Infect Dis. 2006, 6: 1-7. 10.1186/1471-2334-6-1.CrossRef
5.
go back to reference Pedersen M, Brandt CT, Knudsen GM, Østergaard C, Skinhoj P, Skovsted IC, Frimodt-Moller N, Moller K: The effect of S. pneumoniae bacteremia on cerebral blood flow autoregulation in rats. J Cereb Blood Flow Metab. 2008, 28: 126-34. 10.1038/sj.jcbfm.9600514.CrossRefPubMed Pedersen M, Brandt CT, Knudsen GM, Østergaard C, Skinhoj P, Skovsted IC, Frimodt-Moller N, Moller K: The effect of S. pneumoniae bacteremia on cerebral blood flow autoregulation in rats. J Cereb Blood Flow Metab. 2008, 28: 126-34. 10.1038/sj.jcbfm.9600514.CrossRefPubMed
6.
go back to reference Brandt CT, Holm D, Liptrot M, Østergaard C, Lundgren JD, Frimodt-Moller N, Skovsted IC, Rowland IJ: Impact of Bacteremia on the Pathogenesis of Experimental Pneumococcal Meningitis. J Infect Dis. 2008, 197: 235-44. 10.1086/524874.CrossRefPubMed Brandt CT, Holm D, Liptrot M, Østergaard C, Lundgren JD, Frimodt-Moller N, Skovsted IC, Rowland IJ: Impact of Bacteremia on the Pathogenesis of Experimental Pneumococcal Meningitis. J Infect Dis. 2008, 197: 235-44. 10.1086/524874.CrossRefPubMed
7.
go back to reference 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: 265-74. 10.1097/00005072-199903000-00006.CrossRefPubMed 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: 265-74. 10.1097/00005072-199903000-00006.CrossRefPubMed
8.
go back to reference Grandgirard D, Leib SL: Strategies to prevent neuronal damage in paediatric bacterial meningitis. Curr Opin Pediatr. 2006, 18: 112-8. 10.1097/01.mop.0000193292.09894.b7.CrossRefPubMed Grandgirard D, Leib SL: Strategies to prevent neuronal damage in paediatric bacterial meningitis. Curr Opin Pediatr. 2006, 18: 112-8. 10.1097/01.mop.0000193292.09894.b7.CrossRefPubMed
9.
go back to reference Braun JS, Sublett JE, Freyer D, Mitchell TJ, Cleveland JL, Tuomanen EI, Weber JR: Pneumococcal pneumolysin and H(2)O(2) mediate brain cell apoptosis during meningitis. J Clin Invest. 2002, 109: 19-27.CrossRefPubMedPubMedCentral Braun JS, Sublett JE, Freyer D, Mitchell TJ, Cleveland JL, Tuomanen EI, Weber JR: Pneumococcal pneumolysin and H(2)O(2) mediate brain cell apoptosis during meningitis. J Clin Invest. 2002, 109: 19-27.CrossRefPubMedPubMedCentral
10.
go back to reference Leib SL, Clements JM, Lindberg RL, Heimgartner C, Loeffler JM, Pfister LA, Tauber MG, Leppert D: Inhibition of matrix metalloproteinases and tumour necrosis factor alpha converting enzyme as adjuvant therapy in pneumococcal meningitis. Brain. 2001, 124: 1734-42. 10.1093/brain/124.9.1734.CrossRefPubMed Leib SL, Clements JM, Lindberg RL, Heimgartner C, Loeffler JM, Pfister LA, Tauber MG, Leppert D: Inhibition of matrix metalloproteinases and tumour necrosis factor alpha converting enzyme as adjuvant therapy in pneumococcal meningitis. Brain. 2001, 124: 1734-42. 10.1093/brain/124.9.1734.CrossRefPubMed
11.
go back to reference Leib SL, Kim YS, Chow LL, Sheldon RA, Tauber MG: 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: 2632-9. 10.1172/JCI119084.CrossRefPubMedPubMedCentral Leib SL, Kim YS, Chow LL, Sheldon RA, Tauber MG: 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: 2632-9. 10.1172/JCI119084.CrossRefPubMedPubMedCentral
12.
go back to reference Orihuela CJ, Fillon S, Smith-Sielicki SH, El Kasmi KC, Gao G, Soulis K, Patil A, Murray PJ, Tuomanen EI: Cell wall-mediated neuronal damage in early sepsis. Infect Immun. 2006, 74: 3783-9. 10.1128/IAI.00022-06.CrossRefPubMedPubMedCentral Orihuela CJ, Fillon S, Smith-Sielicki SH, El Kasmi KC, Gao G, Soulis K, Patil A, Murray PJ, Tuomanen EI: Cell wall-mediated neuronal damage in early sepsis. Infect Immun. 2006, 74: 3783-9. 10.1128/IAI.00022-06.CrossRefPubMedPubMedCentral
13.
go back to reference Brandt CT, Simonsen H, Liptrot M, Sogaard LV, Lundgren JD, Østergaard C, Frimodt-Moller N, Rowland IJ: In vivo study of experimental pneumococcal meningitis using magnetic resonance imaging. BMC Med Imaging. 2008, 8: 1-10.1186/1471-2342-8-1.CrossRefPubMedPubMedCentral Brandt CT, Simonsen H, Liptrot M, Sogaard LV, Lundgren JD, Østergaard C, Frimodt-Moller N, Rowland IJ: In vivo study of experimental pneumococcal meningitis using magnetic resonance imaging. BMC Med Imaging. 2008, 8: 1-10.1186/1471-2342-8-1.CrossRefPubMedPubMedCentral
14.
go back to reference Wellmer A, von Mering M, Spreer A, Diem R, Eiffert H, Noeske C, Bunkowski S, Gold R, Nau R: Experimental pneumococcal meningitis: Impaired clearance of bacteria from the blood due to increased apoptosis in the spleen in Bcl-2-deficient mice. Infect Immun. 2004, 72: 3113-9. 10.1128/IAI.72.6.3113-3119.2004.CrossRefPubMedPubMedCentral Wellmer A, von Mering M, Spreer A, Diem R, Eiffert H, Noeske C, Bunkowski S, Gold R, Nau R: Experimental pneumococcal meningitis: Impaired clearance of bacteria from the blood due to increased apoptosis in the spleen in Bcl-2-deficient mice. Infect Immun. 2004, 72: 3113-9. 10.1128/IAI.72.6.3113-3119.2004.CrossRefPubMedPubMedCentral
15.
go back to reference de Jonge RC, Swart JF, Koomen I, Rombouts SA, Gemke RJ, Barkhof F, van Furth AM: No structural cerebral differences between children with a history of bacterial meningitis and healthy siblings. Acta Paediatr. 2008, 97: 1390-6.PubMed de Jonge RC, Swart JF, Koomen I, Rombouts SA, Gemke RJ, Barkhof F, van Furth AM: No structural cerebral differences between children with a history of bacterial meningitis and healthy siblings. Acta Paediatr. 2008, 97: 1390-6.PubMed
16.
go back to reference Schmidt H, Heimann B, Djukic M, Mazurek C, Fels C, Wallesch CW, Nau R: Neuropsychological sequelae of bacterial and viral meningitis. Brain. 2006, 129: 333-45. 10.1093/brain/awh711.CrossRefPubMed Schmidt H, Heimann B, Djukic M, Mazurek C, Fels C, Wallesch CW, Nau R: Neuropsychological sequelae of bacterial and viral meningitis. Brain. 2006, 129: 333-45. 10.1093/brain/awh711.CrossRefPubMed
17.
go back to reference Loeffler JM, Ringer R, Hablutzel M, Tauber MG, Leib SL: The free radical scavenger alpha-phenyl-tert-butyl nitrone aggravates hippocampal apoptosis and learning deficits in experimental pneumococcal meningitis. J Infect Dis. 2001, 183: 247-52. 10.1086/317921.CrossRefPubMed Loeffler JM, Ringer R, Hablutzel M, Tauber MG, Leib SL: The free radical scavenger alpha-phenyl-tert-butyl nitrone aggravates hippocampal apoptosis and learning deficits in experimental pneumococcal meningitis. J Infect Dis. 2001, 183: 247-52. 10.1086/317921.CrossRefPubMed
18.
go back to reference Pfister LA, Tureen JH, Shaw S, Christen S, Ferriero DM, Tauber MG, Leib SL: Endothelin inhibition improves cerebral blood flow and is neuroprotective in pneumococcal meningitis. Ann Neurol. 2000, 47: 329-35. 10.1002/1531-8249(200003)47:3<329::AID-ANA8>3.0.CO;2-R.CrossRefPubMed Pfister LA, Tureen JH, Shaw S, Christen S, Ferriero DM, Tauber MG, Leib SL: Endothelin inhibition improves cerebral blood flow and is neuroprotective in pneumococcal meningitis. Ann Neurol. 2000, 47: 329-35. 10.1002/1531-8249(200003)47:3<329::AID-ANA8>3.0.CO;2-R.CrossRefPubMed
19.
go back to reference Gianinazzi C, Grandgirard D, Imboden H, Egger L, Meli DN, Bifrare YD, Joss PC, Tauber MG, Borner C, Leib SL: Caspase-3 mediates hippocampal apoptosis in pneumococcal meningitis. Acta Neuropathol (Berl). 2003, 105: 499-507. Gianinazzi C, Grandgirard D, Imboden H, Egger L, Meli DN, Bifrare YD, Joss PC, Tauber MG, Borner C, Leib SL: Caspase-3 mediates hippocampal apoptosis in pneumococcal meningitis. Acta Neuropathol (Berl). 2003, 105: 499-507.
Metadata
Title
Bacteremia causes hippocampal apoptosis in experimental pneumococcal meningitis
Authors
Christian Østergaard
Stephen L Leib
Ian Rowland
Christian T Brandt
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Infectious Diseases / Issue 1/2010
Electronic ISSN: 1471-2334
DOI
https://doi.org/10.1186/1471-2334-10-1

Other articles of this Issue 1/2010

BMC Infectious Diseases 1/2010 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.