title: Vimentin, a Novel NF-κB Regulator, Is Required for Meningitic Escherichia coli K1-Induced Pathogen Invasion and PMN Transmigration across the Blood-Brain Barrier.
abstract: BACKGROUND
  NF-κB activation, pathogen invasion, polymorphonuclear leukocytes (PMN) transmigration (PMNT) across the blood-brain barrier (BBB) are the pathogenic triad hallmark features of bacterial meningitis, but the mechanisms underlying these events remain largely unknown. Vimentin, which is a novel NF-κB regulator, is the primary receptor for the major Escherichia coli K1 virulence factor IbeA that contributes to the pathogenesis of neonatal bacterial sepsis and meningitis (NSM). We have previously shown that IbeA-induced NF-κB signaling through its primary receptor vimentin as well as its co-receptor PTB-associated splicing factor (PSF) is required for pathogen penetration and leukocyte transmigration across the BBB. This is the first in vivo study to demonstrate how vimentin and related factors contributed to the pathogenic triad of bacterial meningitis.
  
  
  RESULTS
  The role of vimentin in IbeA+ E. coli K1-induced NF-κB activation, pathogen invasion, leukocyte transmigration across the BBB has now been demonstrated by using vimentin knockout (KO) mice. In the in vivo studies presented here, IbeA-induced NF-κB activation, E. coli K1 invasion and polymorphonuclear neutrophil (PMN) transmigration across the BBB were significantly reduced in Vim-/- mice. Decreased neuronal injury in the hippocampal dentate gyrus was observed in Vim-/- mice with meningitis. The major inflammatory regulator α7 nAChR and several signaling molecules contributing to NF-κB activation (p65 and p-CamKII) were significantly reduced in the brain tissues of the Vim-/- mice with E. coli meningitis. Furthermore, Vim KO resulted in significant reduction in neuronal injury and in α7 nAChR-mediated calcium signaling.
  
  
  CONCLUSIONS
  Vimentin, a novel NF-κB regulator, plays a detrimental role in the host defense against meningitic infection by modulating the NF-κB signaling pathway to increase pathogen invasion, PMN recruitment, BBB permeability and neuronal inflammation. Our findings provide the first evidence for Vim-dependent mechanisms underlying the pathogenic triad of bacterial meningitis.
authors.affiliation: Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.|Saban Research Institute of Childrens Hospital Los Angeles, Department of Pediatrics, University of Southern California, Los Angeles, California, United States of America.|Department of Microbiology, School of Public Health and Tropocal Medicine, Southern Medical University, Guangzhou 510515, China.
authors.forename: Sheng-He
authors.initials: SH
authors.lastname: Huang
authors.affiliation: Saban Research Institute of Childrens Hospital Los Angeles, Department of Pediatrics, University of Southern California, Los Angeles, California, United States of America.|Department of Pathology, Southern California Research Center for ALPD and Cirrhosis, the Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Feng
authors.initials: F
authors.lastname: Chi
authors.affiliation: Saban Research Institute of Childrens Hospital Los Angeles, Department of Pediatrics, University of Southern California, Los Angeles, California, United States of America.|Department of Clinic Laboratory, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.affiliation: Saban Research Institute of Childrens Hospital Los Angeles, Department of Pediatrics, University of Southern California, Los Angeles, California, United States of America.|Department of Pediatrics, the Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Bo
authors.affiliation: Saban Research Institute of Childrens Hospital Los Angeles, Department of Pediatrics, University of Southern California, Los Angeles, California, United States of America.|Department of Microbiology, School of Public Health and Tropocal Medicine, Southern Medical University, Guangzhou 510515, China.
authors.forename: Bao
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Saban Research Institute of Childrens Hospital Los Angeles, Department of Pediatrics, University of Southern California, Los Angeles, California, United States of America.|Department of Pediatrics, the Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Li-Qun
authors.initials: LQ
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xuedong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, 5220 MSRB III, 1150 West Medical Center Drive, University of Michigan, Ann Arbor, MI, United States of America.
authors.forename: Nirit
authors.initials: N
authors.lastname: Mor-Vaknin
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, 5220 MSRB III, 1150 West Medical Center Drive, University of Michigan, Ann Arbor, MI, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Markovitz
authors.affiliation: Department of Microbiology, School of Public Health and Tropocal Medicine, Southern Medical University, Guangzhou 510515, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Cao
authors.affiliation: Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Zhou