Host Cytosolic Phospholipase A2 Contributes to Group B Streptococcus Penetration of the Blood-Brain Barrier

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 A2 (cPLA2) 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 cPLA2 significantly decreased GBS invasion of the HBMEC monolayer and penetration into the brain. cPLA2 releases arachidonic acid from membrane phospholipids, and we showed that the contribution of cPLA2 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 C (PKC), as shown by time-dependent PKC activation in response to GBS as well as decreased GBS invasion in HBMEC expressing dominant-negative PKC. PKC activation in response to GBS, however, was abolished by inhibition of cPLA2 and cysteinyl LTs, suggesting that cPLA2 and cysteinyl LTs contribute to type III GBS invasion of the HBMEC monolayer via PKC. These findings demonstrate that specific host factors involving cPLA2 and cysteinyl LTs contribute to type III GBS penetration of the blood-brain barrier and their contribution involves PKC