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

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.

RETRACTED ARTICLE: Cadherin 6 is activated by Epstein–Barr virus LMP1 to mediate EMT and metastasis as an interplay node of multiple pathways in nasopharyngeal carcinoma

“…LMP1 is an oncoprotein of EBV and expresses in most cells of EBV-associated NPC 3 , 24 , 25 . NF-κB, which has central functions in inflammation and cancer development 5 , 26 , is the main pathway activated by LMP1 27 . Besides the transforming ability, LMP1 has been noticed for its induction of invasion and metastasis recently 28 – 30 .…”

Host Cell Vimentin Restrains Toxoplasma gondii Invasion and Phosphorylation of Vimentin is Partially Regulated by Interaction with TgROP18

“…When vimentin was knocked out in HBMEC cells, the infection rate of T. gondii was significantly increased (Figure 4 ). The result, indicating inhibition of host cell vimentin on T. gondii invasion, is opposite to those demonstrated for Escherichia coli K1 and Japanese encephalitis virus infection 31 , 46 , suggesting that vimentin regulates infection of T. gondii and other microbial pathogens by different mechanisms.…”

“…Host cell vimentin has been demonstrated to function in facilitating the infection of some adhesive or invasive microbial pathogens, including P. multocida and African swine fever virus 29 , 30 . Moreover, vimentin is identified as a novel NF-κB regulator and is involved in modulating the NF-κB signaling pathway to influence invasion of pathogens, such as E. coli K1 31 , 32 . The disassembly of vimentin caused by treatment with high concentrations of the phosphatase inhibitors, okadaic acid and calyculin A, suggests that vimentin's assembly/disassembly is regulated by its phosphorylation and dephosphorylation 20 .…”

Invasion of the Brain by Listeria monocytogenes Is Mediated by InlF and Host Cell Vimentin

“…Several studies have suggested that bacterial pathogens use vimentin as a receptor for host cell adherence to mediate pathogen entry into host cells or to cross host barriers ( 24 , 25 , 28 – 30 ). To examine the importance of vimentin for L. monocytogenes invasion in vitro , we performed gentamicin protection assays with MFT-6 (Vim +/+ ) and MFT-16 (Vim −/− ) mouse embryo fibroblasts ( 31 ).…”

“…Indeed, an increasing number of reports have demonstrated a diverse role for vimentin in bacterial infections, primarily in innate host cell defense mechanisms and pathogen adhesion and invasion ( 45 ). Vimentin has been shown to be an important invasion receptor for the IbeA protein of meningitic E. coli K1 and to facilitate invasion of the brain by E. coli K1 in vivo ( 24 , 28 , 46 ). We have shown for the first time that vimentin is exploited by L. monocytogenes for invasion and colonization of the brain in vivo .…”