Pathogenic Triad in Bacterial Meningitis: Pathogen Invasion, NF-κB Activation, and Leukocyte Transmigration that Occur at the Blood-Brain Barrier

Wang, Shifu; Peng, Liang; Gai, Zhongtao; Zhang, Lehai; Jong, Ambrose; Cao, Hong; Huang, Sheng‐He

doi:10.3389/fmicb.2016.00148

Cited by 28 publications

(33 citation statements)

References 106 publications

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“…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 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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“…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 ].…”

Section: Introductionmentioning

confidence: 99%

“…Transmigration of PMNs across the BBB is not only crucial for host defense against pathogens, but it may also cause significant damage to the CNS tissues, which results in devastating neurologic sequelae [ 19 ]. The adhesive interactions between transmigrating leukocytes and endothelial cells are well understood.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…Whether the activation of the p38 pathway provides a potential advantage for these bacterial pathogens in bacterial meningitis is not fully understood. It has been reported that for bacterial meningitis the triad of bacterial invasion, NF-κB activation, and leucocyte transmigration is important where p38 activation might also play a role [48,49]. However, since CxCL-1 and CxCL-2 protein levels were only partially dependent on p38 activity, there might be another yet unrecognized pathway affected by PTx.…”

Section: Discussionmentioning

confidence: 99%

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

Starost

Karassek

Sano

et al. 2016

Toxins

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Pertussis toxin (PTx), the major virulence factor of the whooping cough-causing bacterial pathogen Bordetella 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-causing Escherichia coli K1-RS218 for invasion and translocation across the BBB. Here, we investigated whether PTx and E. coli K1-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 and E. coli K1-RS218 activate MAPK p38, but only E. coli K1-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, whereas E. coli K1-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-causing E. coli support their contributions to pathogen and monocytic THP-1 cells translocation across the BBB.

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“…9,10 Animal model and human post-mortem studies indicate that disease pathogenesis in PM is characterised by a marked inflammatory response to bacterial invasion in the CSF, rather than an inability to mount an immune response. The inflammatory cascade and cytotoxic effects of host pro-inflammatory mediators 11,12 together with bacterial toxins drive tissue damage characterised by apoptotic neuronal cell injury, raised intracranial pressure (ICP), thrombosis, cerebral oedema, and cerebral ischaemia. 13,14 These findings supported the use of anti-inflammatory agents, such as dexamethasone as adjunct therapies for PM.…”

Section: Text Backgroundmentioning

confidence: 99%

Cerebrospinal fluid transcriptional analyses reveals upregulation of IL-17, Type 1 interferon transcriptional pathways and neutrophil persistence genes associated with increased mortality from pneumococcal meningitis in adults

Wall

Guerra-Assunção

Pollara

et al. 2018

Preprint

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Background:Improving outcomes from pneumococcal meningitis (PM), particularly in populations with high HIV prevalence, requires better understanding of host inflammatory responses to infection. Methods:We compared the transcriptome in pre-antibiotic cerebrospinal fluid (CSF) and blood from Malawian adults with PM using RNA sequencing. We used network analyses and cellular/process deconvolution of the transcriptome to identify important patho-physiological associations with outcome. Findings:Blood transcriptional profiles were obtained in 28 patients (21 HIV co-infected; median age 33 years [26-66]; median CSF WCC 28 cells/mm 3 [0-3660]; median bacterial load 4.7x10 6 copies/ml CSF [671-2x10 9 ]; in-hospital mortality 64%), paired CSF profiles were obtained in 13. Marked differences in gene expression by outcome were confined to the CSF. In non-survivors, differentially expressed genes in the CSF were co-correlated in a network of pro-inflammatory gene-clusters enriched for collagen degradation and platelet degranulation. In contrast, CSF gene expression networks from surviving patients were dominated by DNA repair, transcriptional regulation and immunological signalling. CSF expression of gene response-modules for IL-17, Type 1 interferons and IL-10 were enriched in nonsurvivors, expression of cell-specific response-modules did not differ by outcome.However, genes for neutrophil chemotaxis and persistence were highly overexpressed in non-survivors.

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Pathogenic Triad in Bacterial Meningitis: Pathogen Invasion, NF-κB Activation, and Leukocyte Transmigration that Occur at the Blood-Brain Barrier

Cited by 28 publications

References 106 publications

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

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

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

Cerebrospinal fluid transcriptional analyses reveals upregulation of IL-17, Type 1 interferon transcriptional pathways and neutrophil persistence genes associated with increased mortality from pneumococcal meningitis in adults

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