title: Fibronectin mediates Opc-dependent internalization of Neisseria meningitidis in human brain microvascular endothelial cells.
abstract: A central step in the pathogenesis of bacterial meningitis caused by Neisseria meningitidis (the meningococcus) is the interaction of the bacteria with cells of the blood-brain barrier. In the present study, we analysed the invasive potential of two strains representing hypervirulent meningococcal lineages of the ET-5 and ET-37 complex in human brain-derived endothelial cells (HBEMCs). In contrast to previous observations made with epithelial cells and human umbilical vein-derived endothelial cells (HUVECs), significant internalization of encapsulated meningococci by HBMECs was observed. However, this uptake was found only for the ET-5 complex isolate MC 58, and not for an ET-37 complex strain. Furthermore, the uptake of meningococci by HBMECs depended on the presence of human serum, whereas serum of bovine origin did not promote the internalization of meningococci in HBMECs. By mutagenesis experiments, we demonstrate that internalization depended on the expression of the opc gene, which is present in meningococci of the ET-5 complex, but absent in ET-37 complex meningococci. Chromatographic separation of human serum proteins revealed fibronectin as the uptake-promoting serum factor, which binds to HBMECs via alpha 5 beta 1 integrin receptors. These data provide evidence for unique molecular mechanisms of the interaction of meningococci with endothelial cells of the blood-brain barrier and contribute to our understanding of the pathogenesis of meningitis caused by meningococci of different clonal lineages.
authors.affiliation: Institute of Hygiene and Microbiology, University of Würzburg, Germany. aunkmeir@hygiene.uni-wuerzburg.de
authors.forename: Alexandra
authors.initials: A
authors.lastname: Unkmeir
authors.forename: Kirsten
authors.initials: K
authors.lastname: Latsch
authors.forename: Guido
authors.initials: G
authors.lastname: Dietrich
authors.forename: Eva
authors.initials: E
authors.lastname: Wintermeyer
authors.forename: Birgitta
authors.initials: B
authors.lastname: Schinke
authors.forename: Stefan
authors.initials: S
authors.lastname: Schwender
authors.forename: Kwang Sik
authors.initials: KS
authors.lastname: Kim
authors.forename: Martin
authors.initials: M
authors.lastname: Eigenthaler
authors.forename: Matthias
authors.initials: M
authors.lastname: Frosch
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001422:Bacterial Adhesion / Q000187:drug effects; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D001921:Brain / Q000098:blood supply / Q000166:cytology*; D002478:Cells, Cultured; D003470:Culture Media; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism* / Q000494:pharmacology; D017353:Gene Deletion; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009345:Neisseria meningitidis / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity*; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D001425:Bacterial Outer Membrane Proteins; D003470:Culture Media; D005353:Fibronectins; D039081:Integrin alpha5beta1; D009842:Oligopeptides; D010455:Peptides; C074517:opc protein, bacteria; C047981:arginyl-glycyl-aspartic acid; D006493:Heparin