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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1003380&type=printable |
| _version_ | 1826866270586273792 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-15T00:12:17Z |
| format | Article |
| id | doaj.art-1de593b2777a4d21a63b23eefe684163 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2025-02-16T21:57:15Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-1de593b2777a4d21a63b23eefe6841632025-01-16T05:31:00ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742013-01-0196e100338010.1371/journal.ppat.1003380Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage.Carolin WippelJana MaurerChristina FörtschSabrina HuppAlexandra BohlJiangtao MaTimothy J MitchellStephanie BunkowskiWolfgang BrückRoland NauAsparouh I IlievStreptococcus 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1003380&type=printable |
| spellingShingle | 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. PLoS Pathogens |
| title | 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_short | 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 |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1003380&type=printable |
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