title: Escherichia coli K1 Modulates Peroxisome Proliferator-Activated Receptor γ and Glucose Transporter 1 at the Blood-Brain Barrier in Neonatal Meningitis.
abstract: Escherichia coli 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 γ (PPAR-γ) 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-γ 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-γ agonists ameliorate the pathological outcomes of infection by suppressing interleukin 6 production in the brain. Thus, inhibition of PPAR-γ and GLUT-1 by E. coli K1 is a novel pathogenic mechanism in meningitis, and pharmacological upregulation of PPAR-γ and GLUT-1 levels may provide novel therapeutic avenues.
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics Department of Surgery, Children's Hospital Los Angeles.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Krishnan
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics Department of Surgery, Children's Hospital Los Angeles.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Chang
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Stoltz
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics Department of Surgery, Children's Hospital Los Angeles Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: Nemani V
authors.initials: NV
authors.lastname: Prasadarao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000473:pathology*; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation; D051272:Glucose Transporter Type 1 / Q000032:analysis*; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000473:pathology*; D020814:Meningitis, Escherichia coli / Q000473:pathology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D047495:PPAR gamma / Q000032:analysis*; D011956:Receptors, Cell Surface / Q000378:metabolism
chemical_list: D001425:Bacterial Outer Membrane Proteins; C464645:GPATCH1 protein, human; D051272:Glucose Transporter Type 1; D009419:Nerve Tissue Proteins; D047495:PPAR gamma; D011956:Receptors, Cell Surface; C495677:SLC2A1 protein, human; C078167:OMPA outer membrane proteins
keywords: Escherichia coli K1; GLUT-1; PPAR-γ; glucose uptake; meningitis, blood-brain barrier