Vimentin, a Novel NF-κB Regulator, Is Required for Meningitic Escherichia coli K1-Induced Pathogen Invasion and PMN Transmigration across the Blood-Brain Barrier.

Sheng-He Huang,David M Markovitz,Yan-Hong Zhou,Hong Cao,Liang Peng,Li-Qun Liu,Nirit Mor-Vaknin,Bao Zhang,Tao Bo,Feng Chi,Xuedong Wu,Shibo Jiang

doi:10.1371/journal.pone.0162641

Abstract

BackgroundNF-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.Methodology/Principal FindingsThe 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.Conclusion/SignificanceVimentin, 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.

Highlights

Vimentin (Vim) contributes to IbeA-induced pathogenicities in neonatal sepsis and meningitis (NSM), which remains a major cause of death in newborns, especially in low-birth weight infants [1,2,3,4,5,6,7,8,9]
Our studies show that the specific interaction between IbeA and its receptor, Vim, is the upstream signaling event, which is required for the caveolae/LR-dependent entry of E. coli K1 into human BMEC (HBMEC) [6, 8]
The bacterial entry into brain, polymorphonuclear leukocytes (PMN) transmigration across the blood-brain barrier (BBB), and BBB permeability indicated by albumin concentration in cerebrospinal fluid (CSF) were all significantly reduced in vimentin knockout and with IbeA deletion (ZD1) as compared to wild-type mice with E44 infection (Fig 1B, 1C and 1D)

Summary

Introduction

Vimentin (Vim) contributes to IbeA-induced pathogenicities in neonatal sepsis and meningitis (NSM), which remains a major cause of death in newborns, especially in low-birth weight infants [1,2,3,4,5,6,7,8,9]. Several E. coli virulence factors, including ibeA, ibeB, ibeC, aslA, fim, traJ and ompA, have been identified and characterized [1,2,3,4,5,6, 10] Among these genes, the ibeA locus is able to modulate expression of other virulence factors (e.g., aatA, fim, ibeB, ompA and biofilm-associated genes) and predominantly contributes to E. coli K1-caused early-onset human NSM by inducing both pathogen penetration and PMN transmigration (PMNT) across the blood-brain barrier (BBB), which consists mainly of brain microvascular endothelial cells (BMEC) [11,12,13]. The IbeA locus was initially identified as a genetic determinant contributing to E. coli invasion of the BBB, one of the hallmark features of this disease [4, 10,19]

Methods

Results

Conclusion