Group B streptococcal β-hemolysin/cytolysin activates neutrophil signaling pathways in brain endothelium and contributes to development of meningitis

Doran, Kelly S.; Liu, George Y.; Nizet, Victor

doi:10.1172/jci200317335

Cited by 199 publications

(188 citation statements)

References 34 publications

(14 reference statements)

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“…These observations might implicate a mechanism of the bacterium for circumvention of the innate immune system and inhibition of cytokine secretion. Interestingly, the capsule of group B streptococcus, which is also composed of sialic acid, was also assumed to represent a form of molecular mimicry whereby the bacterium resembles host cell surfaces to inhibit immune activation (16).…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Pattern in Human Brain Endothelial Cells in Response to Neisseria meningitidis

et al. 2007

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To extend our knowledge of target proteins in endothelial cells infected with the meningitis-causing pathogen Neisseria meningitidis, we characterized the interaction between the bacterial and human brain microvascular endothelial cell (HBMEC) monolayers. By use of human cDNA microarrays, transcriptional analysis revealed distinct responses to 4 and 8 h of infection. We also addressed the question of whether the major virulence factor of meningococci, i.e., the capsule, influences the host cell response. Of the 1,493 (at 4 h postinfection) and 1,246 (at 8 h postinfection) genes with altered expression upon bacterial contact, about 49.4% and 45%, respectively, depended on capsule expression. In particular, we identified an increase of expression for genes encoding proteins involved in bacterial adhesion and invasion. High levels of apoptosis-related gene (bad, bak, asp, and immediate-early response gene 1) expression could also be detected in infected cells. Further analyses confirmed that HBMECs displayed several hallmarks of apoptosis in response to N. meningitidis infection, namely, phosphatidylserine translocation and activation of caspase 3 and AMP-activated protein kinase ␣. Moreover, several differentially regulated genes not previously known to respond to meningococcal infection were identified. Of these, genes encoding cell adhesion proteins (CD44, CD98, and CD99), genes involved in downstream signaling of integrins (integrin-linked kinase, mitogen-activated protein kinase kinase 1, and mitogen-activated protein kinase kinase kinase 10) as well as negative regulators of these pathways (dualspecificity phosphatases 1, 5, and 14 and G protein pathway suppressor 2), and genes involved in cytoskeleton reorganization (those encoding Arp2/3, p34-arc, actinin alpha 1, vasodilatator-stimulated protein, and Wiskott-Aldrich syndrome protein) were the most prominent. This global transcriptional analysis creates a new platform for further molecular and cellular analysis of the interaction between N. meningitidis and target cells.

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Section: Discussionmentioning

confidence: 99%

Gene Expression Pattern in Human Brain Endothelial Cells in Response to Neisseria meningitidis

et al. 2007

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“…In case of E. coli K1, cytotoxic necrotizing factor-1 (CNF-1) activates RhoA resulting in increased invasion of BMEC in vitro and increased penetration of the BBB in vivo (Khan et al , 2003. In contrast, b hemolysin (bh/c) of GBS (Doran et al 2003;Lembo et al 2010), pneumolysin of S. pneumonia (Zysk et al 2001) and HiB lipopolysaccharide (Patrick et al 1992) all cause apoptosis in brain endothelial cells, which lead to increased BBB permeability and bacterial penetration in vivo.…”

Section: Microbial Adhesion To Bmec and Transcytosis Across The Bbbmentioning

confidence: 99%

Concepts and Mechanisms: Crossing Host Barriers

Doran

Banerjee

Disson

et al. 2013

Cold Spring Harbor Perspectives in Medicine

112

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“…Since meningitis develops following bacterial adhesion to and invasion through the BBB, researchers have used hBMECs to study the pathogenesis of bacterial meningitis [22,26]. Bacterial meningitis pathogens are able to penetrate the BBB transcellularly, paracellularly and/or in infected phagocytes [27].…”

Section: Discussionmentioning

confidence: 99%

“…Bacterial association with and invasion into hBMECs or the human alveolar cell line A549 were quantified as previously described, with minor modifications [12,19,26,52]. hBMECs or A549 cells were seeded at 2 × 10 5 cells into 24-well plates 1 day prior to bacterial infection.…”

Section: Methodsmentioning

confidence: 99%

Competence-induced protein Ccs4 facilitates pneumococcal invasion into brain tissue and virulence in meningitis

et al. 2018

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Streptococcus pneumoniae is a major pathogen that causes pneumonia, sepsis, and meningitis. The candidate combox site 4 (ccs4) gene has been reported to be a pneumococcal competence-induced gene. Such genes are involved in development of S. pneumoniae competence and virulence, though the functions of ccs4 remain unknown. In the present study, the role of Ccs4 in the pathogenesis of pneumococcal meningitis was examined. We initially constructed a ccs4 deletion mutant and complement strains, then examined their association with and invasion into human brain microvascular endothelial cells. Wild-type and Ccs4-complemented strains exhibited significantly higher rates of association and invasion as compared to the ccs4 mutant strain. Deletion of ccs4 did not change bacterial growth activity or expression of NanA and CbpA, known brain endothelial pneumococcal adhesins. Next, mice were infected either intravenously or intranasally with pneumococcal strains. In the intranasal infection model, survival rates were comparable between wild-type strain-infected and ccs4 mutant strain-infected mice, while the ccs4 mutant strain exhibited a lower level of virulence in the intravenous infection model. In addition, at 24 hours after intravenous infection, the bacterial burden in blood was comparable between the wild-type and ccs4 mutant strain-infected mice, whereas the wild-type strain-infected mice showed a significantly higher bacterial burden in the brain. These results suggest that Ccs4 contributes to pneumococcal invasion of host brain tissues and functions as a virulence factor.

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Group B streptococcal β-hemolysin/cytolysin activates neutrophil signaling pathways in brain endothelium and contributes to development of meningitis

Cited by 199 publications

References 34 publications

Gene Expression Pattern in Human Brain Endothelial Cells in Response to Neisseria meningitidis

Gene Expression Pattern in Human Brain Endothelial Cells in Response to Neisseria meningitidis

Concepts and Mechanisms: Crossing Host Barriers

Competence-induced protein Ccs4 facilitates pneumococcal invasion into brain tissue and virulence in meningitis

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