title: Neisseria meningitidis induces platelet inhibition and increases vascular endothelial permeability via nitric oxide regulated pathways.
abstract: Despite antibiotic therapy, infections with  Neisseria meningitidis  still demonstrate a high rate of morbidity and mortality even in developed countries. The fulminant septicaemic course, named Waterhouse-Friderichsen syndrome, with massive haemorrhage into the adrenal glands and widespread petechial bleeding suggest pathophysiological inhibition of platelet function. Our data show that  N. meningitidis  produces the important physiological platelet inhibitor and cardiovascular signalling molecule nitric oxide (NO), also known as endothelium-derived relaxing factor (EDRF).  N. meningitidis -derived NO inhibited ADP-induced platelet aggregation through the activation of soluble guanylyl cyclase (sGC) followed by an increase in platelet cyclic nucleotide levels and subsequent activation of platelet cGMP- and cAMP- dependent protein kinases (PKG and PKA). Furthermore, direct measurement of horseradish peroxidase (HRP) passage through a vascular endothelial cell monolayer revealed that  N. meningitidis  significantly increased endothelial monolayer permeability. Immunfluorescence analysis demonstrated NO dependent disturbances in the structure of endothelial adherens junctions after co-incubation with  N. meningitidis . In contrast to platelet inhibition, the NO effects on HBMEC were not mediated by cyclic nucleotides. Our study provides evidence that NO plays an essential role in the pathophysiology of septicaemic meningococcal infection.
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry /Central Laboratory, University of Wuerzburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Kobsar
authors.forename: Celine
authors.initials: C
authors.lastname: Siauw
authors.forename: Stepan
authors.initials: S
authors.lastname: Gambaryan
authors.forename: Sabrina
authors.initials: S
authors.lastname: Hebling
authors.forename: Christian
authors.initials: C
authors.lastname: Speer
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schubert-Unkmeir
authors.forename: Martin
authors.initials: M
authors.lastname: Eigenthaler
mesh_terms: D022005:Adherens Junctions / Q000648:ultrastructure; D001792:Blood Platelets / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D002199:Capillary Permeability; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D008589:Meningococcal Infections / Q000097:blood / Q000378:metabolism* / Q000382:microbiology; D009345:Neisseria meningitidis / Q000472:pathogenicity / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D010974:Platelet Aggregation; D015398:Signal Transduction
chemical_list: D045462:Endothelium-Dependent Relaxing Factors; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP