Host Cytosolic Phospholipase A2α 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 A(2)alpha (cPLA(2)alpha) 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 cPLA(2)alpha significantly decreased GBS invasion of the HBMEC monolayer and penetration into the brain. cPLA(2)alpha releases arachidonic acid from membrane phospholipids, and we showed that the contribution of cPLA(2)alpha 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 alpha (PKC alpha), as shown by time-dependent PKC alpha activation in response to GBS as well as decreased GBS invasion in HBMEC expressing dominant-negative PKC alpha. PKC alpha activation in response to GBS, however, was abolished by inhibition of cPLA(2)alpha and cysteinyl LTs, suggesting that cPLA(2)alpha and cysteinyl LTs contribute to type III GBS invasion of the HBMEC monolayer via PKC alpha. These findings demonstrate that specific host factors involving cPLA(2)alpha and cysteinyl LTs contribute to type III GBS penetration of the blood-brain barrier and their contribution involves PKC alpha.