title: Pertussis Toxin Exploits Host Cell Signaling Pathways Induced by Meningitis-Causing E. coli K1-RS218 and Enhances Adherence of Monocytic THP-1 Cells to Human Cerebral Endothelial Cells.
abstract: Pertussis toxin (PTx), the major virulence factor of the whooping cough-causing bacterial pathogenBordetella pertussis, permeabilizes the blood-brain barrier (BBB) in vitro and in vivo. Breaking barriers might promote translocation of meningitis-causing bacteria across the BBB, thereby facilitating infection. PTx activates several host cell signaling pathways exploited by the neonatal meningitis-causingEscherichia coliK1-RS218 for invasion and translocation across the BBB. Here, we investigated whether PTx andE. coliK1-RS218 exert similar effects on MAPK p38, NF-κB activation and transcription of downstream targets in human cerebral endothelial TY10 cells using qRT-PCR, Western blotting, and ELISA in combination with specific inhibitors. PTx andE. coliK1-RS218 activate MAPK p38, but onlyE. coliK1-RS218 activates the NF-κB pathway. mRNA and protein levels of p38 and NF-κB downstream targets including IL-6, IL-8, CxCL-1, CxCL-2 and ICAM-1 were increased. The p38 specific inhibitor SB203590 blocked PTx-enhanced activity, whereasE. coliK1-RS218's effects were inhibited by the NF-κB inhibitor Bay 11-7082. Further, we found that PTx enhances the adherence of human monocytic THP-1 cells to human cerebral endothelial TY10 cells, thereby contributing to enhanced translocation. These modulations of host cell signaling pathways by PTx and meningitis-causingE. colisupport their contributions to pathogen and monocytic THP-1 cells translocation across the BBB.
authors.affiliation: Institute of Infectiology, Center of Molecular Biology of Inflammation, Westfälische Wilhelms-Universität Münster, Münster D-48149, Germany. l_star02@uni-muenster.de.
authors.forename: Laura Julia
authors.initials: LJ
authors.lastname: Starost
authors.affiliation: Institute of Infectiology, Center of Molecular Biology of Inflammation, Westfälische Wilhelms-Universität Münster, Münster D-48149, Germany. sascha.karassek@hotmail.com.
authors.forename: Sascha
authors.initials: S
authors.lastname: Karassek
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi, Ube City 755-8505, Japan. yasuteru@yamaguchi-u.ac.jp.
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Sano
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi, Ube City 755-8505, Japan. tkanda@yamaguchi-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanda
authors.affiliation: Pediatric Infectious Diseases Division, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. kwangkim@jhmi.edu.
authors.forename: Kwang Sik
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Institute of Hygiene, Microbial Genome Plasticity-Molecular Infection Biology, Westfälische Wilhelms-Universität Münster, Münster D-48149, Germany. dobrindt@uni-muenster.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dobrindt
authors.affiliation: Institute of Infectiology, Center of Molecular Biology of Inflammation, Westfälische Wilhelms-Universität Münster, Münster D-48149, Germany. rueterc@uni-muenster.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Rüter
authors.affiliation: Institute of Infectiology, Center of Molecular Biology of Inflammation, Westfälische Wilhelms-Universität Münster, Münster D-48149, Germany. infekt@uni-muenster.de.
authors.forename: Marcus Alexander
authors.initials: MA
authors.lastname: Schmidt
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D054022:Cerebrum / Q000166:cytology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004926:Escherichia coli; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D020814:Meningitis, Escherichia coli; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D037342:Pertussis Toxin / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D018799:Intercellular Adhesion Molecule-1; D037342:Pertussis Toxin; D048051:p38 Mitogen-Activated Protein Kinases
keywords: MAPK p38; NF-κB; NMEC; blood–brain barrier; neonatal meningitis-causing E. coli K1-RS218; pertussis toxin