title: Staphylococcal α-hemolysin is neurotoxic and causes lysis of brain cells in vivo and in vitro.
abstract: Formation of a bacterial brain abscess entails loss of brain cells and formation of pus. The mechanisms behind the cell loss are not fully understood. Staphylococcus aureus, a common cause of brain abscesses, produces various exotoxins, including α-hemolysin, which is an important factor in brain abscess formation. α-Hemolysin may cause cytolysis by forming pores in the plasma membrane of various eukaryotic cells. However, whether α-hemolysin causes lysis of brain cells is not known. Nor is it known whether α-hemolysin in the brain causes cell death through pore formation or by acting as a chemoattractant, recruiting leukocytes and causing inflammation. Here we show that α-hemolysin injected into rat brain causes cell damage and edema formation within 30 min. Cell damage was accompanied by an increase in extracellular concentrations of zinc, GABA, glutamate, and other amino acids, indicating plasma membrane damage, but leukocytic infiltration was not seen 0.5-12h after α-hemolysin injection. This was in contrast to injection of S. aureus, which triggered extensive infiltration with neutrophils within 8h. In vitro, α-hemolysin caused concentration-dependent lysis of isolated nerve endings and cultured astrocytes. We conclude that α-hemolysin contributes to the cell death inherent in staphylococcal brain abscess formation as a pore-forming neurotoxin.
authors.affiliation: Department of Neurosurgery, Oslo University Hospital, Oslo, Norway. Electronic address: daniel.dahlberg@ous-hf.no.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dahlberg
authors.affiliation: Norwegian Defence Research Establishment (FFI), Kjeller, Norway. Electronic address: espen.mariussen@ffi.no.
authors.forename: Espen
authors.initials: E
authors.lastname: Mariussen
authors.affiliation: Department of Pathology (Neuropathology), Oslo University Hospital, Oslo, Norway. Electronic address: i.l.goverud@medisin.uio.no.
authors.forename: Ingeborg Løstegaard
authors.initials: IL
authors.lastname: Goverud
authors.affiliation: Department of Microbiology, Oslo University Hospital, Oslo, Norway. Electronic address: tone.tonjum@medisin.uio.no.
authors.forename: Tone
authors.initials: T
authors.lastname: Tønjum
authors.affiliation: Department of Pathology (Neuropathology), Oslo University Hospital, Oslo, Norway. Electronic address: jan.mahlen@medisin.uio.no.
authors.forename: Jan
authors.initials: J
authors.lastname: Mæhlen
authors.affiliation: Department of Pathology (Neuropathology), Oslo University Hospital, Oslo, Norway. Electronic address: e.a.antal@medisin.uio.no.
authors.forename: Ellen-Ann
authors.initials: EA
authors.lastname: Antal
authors.affiliation: Norwegian Defence Research Establishment (FFI), Kjeller, Norway; Department of Neurology, Oslo University Hospital, Oslo, Norway. Electronic address: bjornar.hassel@ffi.no.
authors.forename: Bjørnar
authors.initials: B
authors.lastname: Hassel
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001427:Bacterial Toxins / Q000633:toxicity*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000139:chemically induced / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000378:metabolism; D006460:Hemolysin Proteins / Q000633:toxicity*; D007964:Leukocytosis / Q000139:chemically induced / Q000473:pathology; D008297:Male; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D017729:Presynaptic Terminals / Q000187:drug effects / Q000473:pathology; D017208:Rats, Wistar; D013997:Time Factors; D015032:Zinc / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D006460:Hemolysin Proteins; C021091:staphylococcal alpha-toxin; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D015032:Zinc
keywords: Brain abscess; Glutamate; Zinc; α-Hemolysin; α-Toxin