title: Astrocytic tissue remodeling by the meningitis neurotoxin pneumolysin facilitates pathogen tissue penetration and produces interstitial brain edema.
abstract: Astrocytes represent a major component of brain tissue and play a critical role in the proper functioning and protection of the brain. Streptococcus pneumoniae, the most common cause of bacterial meningitis, has a high lethality and causes serious disabilities in survivors. Pneumolysin (PLY), a member of the cholesterol-dependent cytolysin group and a major S. pneumoniae neurotoxin, causes deterioration over the course of experimental S. pneumoniae meningitis. At disease-relevant sub-lytic concentrations, PLY produces actin and tubulin reorganization and astrocyte cell shape changes in vitro. In this article, we show that sub-lytic amounts of PLY remodel brain tissue and produce astrocytic process retraction, cortical astroglial reorganization and increased interstitial fluid retention, which is manifested as tissue edema. These changes caused increased tissue permeability to macromolecules and bacteria. The pore-forming capacity of PLY remained necessary for these changes because none of the nonpore-forming mutants were capable of producing similar effects. We suggest that PLY can increase the permeability of brain tissue toward pathogenic factors and bacteria in the course of meningitis, thus contributing to the deterioration caused by the disease.
authors: DFG Membrane/Cytoskeleton Interaction Group, Institute of Pharmacology and Toxicology & Rudolf Virchow Center for Experimental Medicine, University of Würzburg, Versbacherstr. 9, 97078 Würzburg, Germany.
authors: Sabrina
authors: S
authors: Hupp
authors: Vera
authors: V
authors: Heimeroth
authors: Carolin
authors: C
authors: Wippel
authors: Christina
authors: C
authors: Förtsch
authors: Jiangtao
authors: J
authors: Ma
authors: Timothy J
authors: TJ
authors: Mitchell
authors: Asparouh I
authors: AI
authors: Iliev
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects*; D001426:Bacterial Proteins / Q000633:toxicity; D001921:Brain / Q000166:cytology*; D001929:Brain Edema / Q000139:chemically induced*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045604:Extracellular Fluid / Q000187:drug effects / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008581:Meningitis / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009498:Neurotoxins / Q000633:toxicity*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D013296:Streptococcus pneumoniae / Q000737:chemistry*; D013301:Streptolysins / Q000633:toxicity*; D014404:Tubulin / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D009498:Neurotoxins; D013301:Streptolysins; D014404:Tubulin; C032290:plY protein, Streptococcus pneumoniae; D007770:L-Lactate Dehydrogenase