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.

Specific DNA recognition mediated by a type IV pilin

“…E. coli BL21(DE3) was used for protein expression and purification experiments. Derivatives of the pMAL-p2X expression vector (New England Biolabs) encoding fusions between MBP and the soluble portions of ComP, PilE, PilV, and PilX (ComP , PilE , PilV , and PilX 39-162 ) have been described previously (19,34). All of the fusion proteins are directed to the periplasm, which is important for disulfide bond formation, and the MBP can be cleaved off by factor Xa, giving soluble proteins with four vector-derived N-terminal residues (ISEF).…”

α-arrestin 1 (ARRDC1) and β-arrestins cooperate to mediate Notch degradation in mammals

“…1C) was sufficient to allow some binding of Notch to Itch. To demonstrate this, we knocked down the endogenous b-arrestin 1 and barrestin 2 as described previously (Coureuil et al, 2010). The efficiency of siRNA targeting b-arrestins (sib-arr) was confirmed by western blot (Fig.…”

Concepts and Mechanisms: Crossing Host Barriers

“…E. coli K1 OmpA initiates a signaling process that leads to the dissociation of b-catenins from cadherins which further results in disruption of barrier integrity . The type-IV pili of N. meningitides, on the other hand, stimulates the b2-adrenoceptor/b-arrestin signaling pathway in endothelial cells, leading to recruitment of the Par3/Par6/PKCz polarity complex and delocalization of junctional proteins which result in anatomical gaps that are used by the bacteria to penetrate into the CNS (Coureuil et al 2009(Coureuil et al , 2010. Human immunodeficiency virus (HIV) envelope glycoprotein gp120 has also been shown to increase BBB permeability by interacting with endothelial trans-membrane coreceptor CCR5 and CXCR4 (Kanmogne et al 2007).…”