title: Host cytosolic phospholipase A₂α contributes to group B Streptococcus penetration of the blood-brain barrier.
abstract: Group B Streptococcus (GBS) is the most common bacterium causing neonatal meningitis, and neonatal GBS meningitis continues to be an important cause of mortality and morbidity. Here we provide the first direct evidence that host cytosolic phospholipase A₂α (cPLA₂α) contributes to type III GBS invasion of human brain microvascular endothelial cells (HBMEC), which constitute the blood-brain barrier and penetration into the brain, the key step required for the development of GBS meningitis. This was shown by our demonstration that pharmacological inhibition and gene deletion of cPLA₂α significantly decreased GBS invasion of the HBMEC monolayer and penetration into the brain. cPLA₂α releases arachidonic acid from membrane phospholipids, and we showed that the contribution of cPLA₂α to GBS invasion of HBMEC involved lipoxygenated metabolites of arachidonic acid, cysteinyl leukotrienes (LTs). In addition, type III GBS invasion of the HBMEC monolayer involves protein kinase Cα (PKCα), as shown by time-dependent PKCα activation in response to GBS as well as decreased GBS invasion in HBMEC expressing dominant-negative PKCα. PKCα activation in response to GBS, however, was abolished by inhibition of cPLA₂α and cysteinyl LTs, suggesting that cPLA₂α and cysteinyl LTs contribute to type III GBS invasion of the HBMEC monolayer via PKCα. These findings demonstrate that specific host factors involving cPLA₂α and cysteinyl LTs contribute to type III GBS penetration of the blood-brain barrier and their contribution involves PKCα.
authors.affiliation: Department of Pediatrics, Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Maruvada
authors.forename: Longkun
authors.initials: L
authors.lastname: Zhu
authors.forename: Donna
authors.initials: D
authors.lastname: Pearce
authors.forename: Adam
authors.initials: A
authors.lastname: Sapirstein
authors.forename: Kwang Sik
authors.initials: KS
authors.lastname: Kim
mesh_terms: D016718:Arachidonic Acid / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000382:microbiology*; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D002478:Cells, Cultured; D003545:Cysteine / Q000378:metabolism*; D042783:Endothelial Cells / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000382:microbiology; D004789:Enzyme Activation; D006801:Humans; D015289:Leukotrienes / Q000378:metabolism*; D008833:Microcirculation; D054510:Phospholipases A2, Cytosolic / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D013292:Streptococcus agalactiae / Q000378:metabolism / Q000472:pathogenicity*
chemical_list: D015289:Leukotrienes; C112381:cysteinyl-leukotriene; D016718:Arachidonic Acid; D051571:Protein Kinase C-alpha; D054510:Phospholipases A2, Cytosolic; D003545:Cysteine