title: Meningococcus Hijacks a β2-adrenoceptor/β-Arrestin pathway to cross brain microvasculature endothelium.
abstract: Following pilus-mediated adhesion to human brain endothelial cells, meningococcus (N. meningitidis), the bacterium causing cerebrospinal meningitis, initiates signaling cascades, which eventually result in the opening of intercellular junctions, allowing meningeal colonization. The signaling receptor activated by the pathogen remained unknown. We report that N. meningitidis specifically stimulates a biased β2-adrenoceptor/β-arrestin signaling pathway in endothelial cells, which ultimately traps β-arrestin-interacting partners, such as the Src tyrosine kinase and junctional proteins, under bacterial colonies. Cytoskeletal reorganization mediated by β-arrestin-activated Src stabilizes bacterial adhesion to endothelial cells, whereas β-arrestin-dependent delocalization of junctional proteins results in anatomical gaps used by bacteria to penetrate into tissues. Activation of β-adrenoceptor endocytosis with specific agonists prevents signaling events downstream of N. meningitidis adhesion and inhibits bacterial crossing of the endothelial barrier. The identification of the mechanism used for hijacking host cell signaling machineries opens perspectives for treatment and prevention of meningococcal infection.
authors.affiliation: Université Paris Descartes, Faculté de Médecine, 75006 Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Coureuil
authors.forename: Hervé
authors.initials: H
authors.lastname: Lécuyer
authors.forename: Mark G H
authors.initials: MG
authors.lastname: Scott
authors.forename: Cédric
authors.initials: C
authors.lastname: Boularan
authors.forename: Hervé
authors.initials: H
authors.lastname: Enslen
authors.forename: Magali
authors.initials: M
authors.lastname: Soyer
authors.forename: Guillain
authors.initials: G
authors.lastname: Mikaty
authors.forename: Sandrine
authors.initials: S
authors.lastname: Bourdoulous
authors.forename: Xavier
authors.initials: X
authors.lastname: Nassif
authors.forename: Stefano
authors.initials: S
authors.lastname: Marullo
mesh_terms: D019390:Arrestins / Q000378:metabolism*; D001422:Bacterial Adhesion; D001812:Blood-Brain Barrier; D001921:Brain / Q000382:microbiology*; D002460:Cell Line; D042783:Endothelial Cells / Q000382:microbiology*; D006801:Humans; D008589:Meningococcal Infections / Q000378:metabolism* / Q000382:microbiology; D009345:Neisseria meningitidis / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D011943:Receptors, Adrenergic, beta; D000071557:beta-Arrestins