Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage.

Streptococcus pneumoniae (pneumococcal) meningitis is a common bacterial infection of the brain. The cholesterol-dependent cytolysin pneumolysin represents a key factor, determining the neuropathogenic potential of the pneumococci. Here, we demonstrate selective synaptic loss within the superficial...

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Autores principales:	Carolin Wippel, Jana Maurer, Christina Förtsch, Sabrina Hupp, Alexandra Bohl, Jiangtao Ma, Timothy J Mitchell, Stephanie Bunkowski, Wolfgang Brück, Roland Nau, Asparouh I Iliev
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1de593b2777a4d21a63b23eefe684163
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spelling	oai:doaj.org-article:1de593b2777a4d21a63b23eefe6841632021-11-18T06:05:33ZBacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage.1553-73661553-737410.1371/journal.ppat.1003380https://doaj.org/article/1de593b2777a4d21a63b23eefe6841632013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23785278/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Streptococcus pneumoniae (pneumococcal) meningitis is a common bacterial infection of the brain. The cholesterol-dependent cytolysin pneumolysin represents a key factor, determining the neuropathogenic potential of the pneumococci. Here, we demonstrate selective synaptic loss within the superficial layers of the frontal neocortex of post-mortem brain samples from individuals with pneumococcal meningitis. A similar effect was observed in mice with pneumococcal meningitis only when the bacteria expressed the pore-forming cholesterol-dependent cytolysin pneumolysin. Exposure of acute mouse brain slices to only pore-competent pneumolysin at disease-relevant, non-lytic concentrations caused permanent dendritic swelling, dendritic spine elimination and synaptic loss. The NMDA glutamate receptor antagonists MK801 and D-AP5 reduced this pathology. Pneumolysin increased glutamate levels within the mouse brain slices. In mouse astrocytes, pneumolysin initiated the release of glutamate in a calcium-dependent manner. We propose that pneumolysin plays a significant synapto- and dendritotoxic role in pneumococcal meningitis by initiating glutamate release from astrocytes, leading to subsequent glutamate-dependent synaptic damage. We outline for the first time the occurrence of synaptic pathology in pneumococcal meningitis and demonstrate that a bacterial cytolysin can dysregulate the control of glutamate in the brain, inducing excitotoxic damage.Carolin WippelJana MaurerChristina FörtschSabrina HuppAlexandra BohlJiangtao MaTimothy J MitchellStephanie BunkowskiWolfgang BrückRoland NauAsparouh I IlievPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 6, p e1003380 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Carolin Wippel Jana Maurer Christina Förtsch Sabrina Hupp Alexandra Bohl Jiangtao Ma Timothy J Mitchell Stephanie Bunkowski Wolfgang Brück Roland Nau Asparouh I Iliev Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage.
description	Streptococcus pneumoniae (pneumococcal) meningitis is a common bacterial infection of the brain. The cholesterol-dependent cytolysin pneumolysin represents a key factor, determining the neuropathogenic potential of the pneumococci. Here, we demonstrate selective synaptic loss within the superficial layers of the frontal neocortex of post-mortem brain samples from individuals with pneumococcal meningitis. A similar effect was observed in mice with pneumococcal meningitis only when the bacteria expressed the pore-forming cholesterol-dependent cytolysin pneumolysin. Exposure of acute mouse brain slices to only pore-competent pneumolysin at disease-relevant, non-lytic concentrations caused permanent dendritic swelling, dendritic spine elimination and synaptic loss. The NMDA glutamate receptor antagonists MK801 and D-AP5 reduced this pathology. Pneumolysin increased glutamate levels within the mouse brain slices. In mouse astrocytes, pneumolysin initiated the release of glutamate in a calcium-dependent manner. We propose that pneumolysin plays a significant synapto- and dendritotoxic role in pneumococcal meningitis by initiating glutamate release from astrocytes, leading to subsequent glutamate-dependent synaptic damage. We outline for the first time the occurrence of synaptic pathology in pneumococcal meningitis and demonstrate that a bacterial cytolysin can dysregulate the control of glutamate in the brain, inducing excitotoxic damage.
format	article
author	Carolin Wippel Jana Maurer Christina Förtsch Sabrina Hupp Alexandra Bohl Jiangtao Ma Timothy J Mitchell Stephanie Bunkowski Wolfgang Brück Roland Nau Asparouh I Iliev
author_facet	Carolin Wippel Jana Maurer Christina Förtsch Sabrina Hupp Alexandra Bohl Jiangtao Ma Timothy J Mitchell Stephanie Bunkowski Wolfgang Brück Roland Nau Asparouh I Iliev
author_sort	Carolin Wippel
title	Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage.
title_short	Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage.
title_full	Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage.
title_fullStr	Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage.
title_full_unstemmed	Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage.
title_sort	bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/1de593b2777a4d21a63b23eefe684163
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Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage.

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