Escherichia coli K1 Modulates Peroxisome Proliferator-Activated Receptor ϒ and Glucose Transporter 1 at the Blood-Brain Barrier in Neonatal Meningitis

Escherichia colt K1 meningitis continues to be a major threat to neonatal health. Previous studies demonstrated that outer membrane protein A (OmpA) of E. coli K1 interacts with endothelial cell glycoprotein 96 (Ecgp96) in the blood-brain barrier to enter the central nervous system. Here we show that the interaction between OmpA and Ecgp96 downregulates peroxisome proliferator-activated receptor ϒ (PPAR-ϒ) and glucose transporter 1 (GLUT-1) levels in human brain microvascular endothelial cells, causing disruption of barrier integrity and inhibition of glucose uptake. The suppression of PPAR-ϒ and GLUT-1 by the bacteria in the brain microvessels of newborn mice causes extensive pathophysiology owing to interleukin 6 production. Pretreatment with partial or selective PPAR-ϒ agonists ameliorate the pathological outcomes of infection by suppressing interleukin 6 production in the brain. Thus, inhibition of PPAR-ϒ and GLUT-1 by E. colt K1 is a novel pathogenic mechanism in meningitis, and pharmacological upregulation of PPAR-ϒ and GLUT-1 levels may provide novel therapeutic avenues.