title: Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage.
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.
authors.affiliation: DFG Membrane/Cytoskeleton Interaction Group, Institute of Pharmacology and Toxicology & Rudolf Virchow Center for Experimental Medicine, University of Würzburg, Würzburg, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Wippel
authors.forename: Jana
authors.initials: J
authors.lastname: Maurer
authors.forename: Christina
authors.initials: C
authors.lastname: Förtsch
authors.forename: Sabrina
authors.initials: S
authors.lastname: Hupp
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bohl
authors.forename: Jiangtao
authors.initials: J
authors.lastname: Ma
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mitchell
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bunkowski
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.forename: Roland
authors.initials: R
authors.lastname: Nau
authors.forename: Asparouh I
authors.initials: AI
authors.lastname: Iliev
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005625:Frontal Lobe / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008586:Meningitis, Pneumococcal / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D013301:Streptolysins / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology
chemical_list: D001426:Bacterial Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; D018698:Glutamic Acid; D016291:Dizocilpine Maleate