title: Sphingosine 1-Phosphate Activation of EGFR As a Novel Target for Meningitic Escherichia coli Penetration of the Blood-Brain Barrier.
abstract: Central nervous system (CNS) infection continues to be an important cause of mortality and morbidity, necessitating new approaches for investigating its pathogenesis, prevention and therapy. Escherichia coli is the most common Gram-negative bacillary organism causing meningitis, which develops following penetration of the blood-brain barrier (BBB). By chemical library screening, we identified epidermal growth factor receptor (EGFR) as a contributor to E. coli invasion of the BBB in vitro. Here, we obtained the direct evidence that CNS-infecting E. coli exploited sphingosine 1-phosphate (S1P) for EGFR activation in penetration of the BBB in vitro and in vivo. We found that S1P was upstream of EGFR and participated in EGFR activation through S1P receptor as well as through S1P-mediated up-regulation of EGFR-related ligand HB-EGF, and blockade of S1P function through targeting sphingosine kinase and S1P receptor inhibited EGFR activation, and also E. coli invasion of the BBB. We further found that both S1P and EGFR activations occurred in response to the same E. coli proteins (OmpA, FimH, NlpI), and that S1P and EGFR promoted E. coli invasion of the BBB by activating the downstream c-Src. These findings indicate that S1P and EGFR represent the novel host targets for meningitic E. coli penetration of the BBB, and counteracting such targets provide a novel approach for controlling E. coli meningitis in the era of increasing resistance to conventional antibiotics.
authors.affiliation: Department of Pediatrics, Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China.
authors.forename: Xiangru
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Ravi
authors.initials: R
authors.lastname: Maruvada
authors.affiliation: Division of Cardiovascular Medicine, The Gill Heart Institute, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.affiliation: Department of Biological Chemistry, Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Michael J
authors.identifier: http://orcid.org/0000-0003-2349-8414
authors.initials: MJ
authors.lastname: Wolfgang
authors.affiliation: Department of Chemistry and Biochemistry, Queens College, The City University of New York, Flushing, New York, United States of America.
authors.forename: Dong Jae
authors.initials: DJ
authors.lastname: Baek
authors.affiliation: Department of Chemistry and Biochemistry, Queens College, The City University of New York, Flushing, New York, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.affiliation: Department of Pediatrics, Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Kwang Sik
authors.initials: KS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000382:microbiology; D015153:Blotting, Western; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism* / Q000382:microbiology; D066246:ErbB Receptors / Q000378:metabolism*; D004926:Escherichia coli; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D008246:Lysophospholipids / Q000378:metabolism*; D013058:Mass Spectrometry; D020814:Meningitis, Escherichia coli / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014162:Transfection
chemical_list: D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; C512478:EGFR protein, human; D066246:ErbB Receptors; D013110:Sphingosine