Sphingosine 1-Phosphate Activation of EGFR As a Novel Target for Meningitic Escherichia coli Penetration of the Blood-Brain Barrier

PLoS Pathogens

Dong Jae Baek¹  Kwang Sik Kim²  Robert Bittman²  Andrew J. Morris³  Xiangru Wang³  Michael J. Wolfgang⁴  Jun O. Liu⁵  Ravi Maruvada⁶ 

[1] Department of Biological Chemistry, Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America;Department of Chemistry and Biochemistry, Queens College, The City University of New York, Flushing, New York, United States of America;Department of Pediatrics, Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America;Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America;Division of Cardiovascular Medicine, The Gill Heart Institute, University of Kentucky, Lexington, Kentucky, United States of America;State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China

关键词: Meningitis;    Escherichia coli infections;    Tyrosine kinases;    EGFR signaling;    Host cells;    Deletion mutagenesis;    Transactivation;    Escherichia coli;   

DOI  :  10.1371/journal.ppat.1005926

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY