TY - JOUR A1 - Wippel, Carolin A1 - Maurer, Jana A1 - Fortsch, Christina A1 - Hupp, Sabrina A1 - Bohl, Alexandra A1 - Ma, Jiangtao A1 - Mitchell, Timothy J. A1 - Bunkowski, Stephanie A1 - Brück, Wolfgang A1 - Nau, Roland A1 - Iliev, Asparouh I. T1 - Bacterial Cytolysin during Meningitis Disrupts the Regulation of Glutamate in the Brain, Leading to Synaptic Damage JF - PLoS Pathogens N2 - Abstract 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. Author Summary Bacterial meningitis is one of the most devastating brain diseases. Among the bacteria that cause meningitis, Streptococcus pneumoniae is the most common. Meningitis predominantly affects children, especially in the Third World, and most of them do not survive. Those that do survive often suffer permanent brain damage and hearing problems. The exact morphological substrates of brain damage in Streptococcus pneumoniae meningitis remain largely unknown. In our experiments, we found that the brain cortex of patients with meningitis demonstrated a loss of synapses (the contact points among neurons, responsible for the processes of learning and memory), and we identified the major pneumococcal neurotoxin pneumolysin as a sufficient cause of this loss. The effect was not direct but was mediated by the brain neurotransmitter glutamate, which was released upon toxin binding by one of the non-neuronal cell types of the brain – the astrocytes. Pneumolysin initiated calcium influx in astrocytes and subsequent glutamate release. Glutamate damaged the synapses via NMDA-receptors – a mechanism similar to the damage occurring in brain ischemia. Thus, we show that synaptic loss is present in pneumococcal meningitis, and we identify the toxic bacterial protein pneumolysin as the major factor in this process. These findings alter our understanding of bacterial meningitis and establish new therapeutic strategies for this fatal disease. KW - synapses KW - brain damage KW - astrocytes KW - neuronal dendrites KW - meningitis KW - glutamate KW - bacterial meningitis KW - neocortex Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130462 VL - 9 IS - 6 ER - TY - BOOK A1 - Linzner, Felix A1 - Hegeler, Lorenz A1 - Kernwein, Leon A1 - Bohl, Pauline A1 - Kizilarslan, Melis A1 - Sudhop, Felix A1 - Nguyen-Xuan, Quang A1 - Macharowski, Maximilian A1 - Eßlinger, Elmar A1 - Waldmann, Nils A1 - Erl, Veronika A1 - Heimberger Ramírez, Alexandra A1 - Renner, Jana ED - Linzner, Felix T1 - Gelebte Utopien - Siedlungsprojekte der Lebensreform T1 - Lived utopias - settlement projects of the Lebensreform movement N2 - Ab der Mitte des 19. Jahrhunderts verdichten sich im deutschsprachigen Raum Reformbestrebungen, die unter dem Sammelbegriff Lebensreform wirkmächtig werden. Vor allem Vertreter*innen des Bürgertums erproben und entwerfen Gesellschaftsformen und Lebensweisen, die sie als Antwort auf eine als krisenhaft empfundene Moderne begreifen. Gegen Industrialisierung, Urbanisierung und immer rasanter wirkende Veränderungen der Alltagswelten wird eine vermeintlich „natürliche“ Lebensweise angestrebt. Als gelebte Utopien sind es Siedlungsprojekte, die auf eine praktische Umsetzung jenes Gedankengutes abzielen. Studierende des Lehrstuhls Europäische Ethnologie / Volkskunde der Universität Würzburghaben sich unter der Anleitung von Felix Linzner diesen Experimentierfeldern der Moderne gewidmet. Der Band dokumentiert die historisch-kulturwissenschaftliche Bearbeitung einzelner Siedlungsprojekte sowie die Arbeit im Archiv und die Präsentation der Ergebnisse in Form zweier Ausstellungen. N2 - From the middle of the 19th century, reform efforts intensified in the German-speaking area. These reform movements became popular under the collective term “Lebensreform”. Representatives of the bourgeoisie try out and design forms of society and lifestyles that they understand as an answer to a modernity that is perceived as crisis-ridden. A supposedly “natural” way of life is aspired to counter industrialization, urbanization and increasingly rapid changes in everyday life. As lived utopias, they are settlement projects that aim to put these ideas into practice. Students of the Chair of European Ethnology at the University of Würzburg have focused these experimental fields of modernity in a project seminar led by Felix Linzner. The volume documents the students’ engagement with individual settlement projects, cultural-historical methods and perspectives as well as their work in the archive. It shows how these explorations became results that were presented to the public in two exhibitions. T3 - Würzburger Studien zur Europäischen Ethnologie - 10 KW - Lebensreform KW - Körperkultur KW - Historische Anthropologie KW - Kulturgeschichte Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245616 SN - 2511-9486 ER -