title: Differential activation of acid sphingomyelinase and ceramide release determines invasiveness of Neisseria meningitidis into brain endothelial cells.
abstract: The interaction with brain endothelial cells is central to the pathogenicity of Neisseria meningitidis infections. Here, we show that N. meningitidis causes transient activation of acid sphingomyelinase (ASM) followed by ceramide release in brain endothelial cells. In response to N. meningitidis infection, ASM and ceramide are displayed at the outer leaflet of the cell membrane and condense into large membrane platforms which also concentrate the ErbB2 receptor. The outer membrane protein Opc and phosphatidylcholine-specific phospholipase C that is activated upon binding of the pathogen to heparan sulfate proteoglycans, are required for N. meningitidis-mediated ASM activation. Pharmacologic or genetic ablation of ASM abrogated meningococcal internalization without affecting bacterial adherence. In accordance, the restricted invasiveness of a defined set of pathogenic isolates of the ST-11/ST-8 clonal complex into brain endothelial cells directly correlated with their restricted ability to induce ASM and ceramide release. In conclusion, ASM activation and ceramide release are essential for internalization of Opc-expressing meningococci into brain endothelial cells, and this segregates with invasiveness of N. meningitidis strains.
authors.affiliation: Institute of Hygiene and Microbiology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Simonis
authors.affiliation: Institute of Hygiene and Microbiology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Hebling
authors.affiliation: Department of Molecular Medicine, University of Essen, Essen, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.affiliation: Institute for Virology and Immunbiology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Schneider-Schaulies
authors.affiliation: Institute of Hygiene and Microbiology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schubert-Unkmeir
mesh_terms: D001422:Bacterial Adhesion / Q000187:drug effects; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008585:Meningitis, Meningococcal / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D009154:Mutation; D009345:Neisseria meningitidis / Q000472:pathogenicity* / Q000502:physiology; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013499:Surface Properties / Q000187:drug effects; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D002518:Ceramides; D004791:Enzyme Inhibitors; C074517:opc protein, bacteria; D010738:Type C Phospholipases; C543066:SMPD1 protein, human; D013108:Sphingomyelin Phosphodiesterase; C105598:phosphatidylcholine-specific phospholipase C