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Group B streptococcal β-hemolysin/cytolysin activates neutrophil signaling pathways in brain endothelium and contributes to development of meningitis
Kelly S. Doran, … , George Y. Liu, Victor Nizet
Kelly S. Doran, … , George Y. Liu, Victor Nizet
Published September 1, 2003
Citation Information: J Clin Invest. 2003;112(5):736-744. https://doi.org/10.1172/JCI17335.
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Article Infectious disease Article has an altmetric score of 12

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

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Abstract

Meningitis occurs when blood-borne pathogens cross the blood-brain barrier (BBB) in a complex interplay between endothelial cells and microbial gene products. We sought to understand the initial response of the BBB to the human meningeal pathogen group B Streptococcus (GBS) and the organism’s major virulence factors, the exopolysaccharide capsule and the β-hemolysin/cytolysin toxin (β-h/c). Using oligonucleotide microarrays, we found that GBS infection of human brain microvascular endothelial cells (HBMEC) induced a highly specific and coordinate set of genes including IL-8, Groα, Groβ, IL-6, GM-CSF, myeloid cell leukemia sequence-1 (Mcl-1), and ICAM-1, which act to orchestrate neutrophil recruitment, activation, and enhanced survival. Most strikingly, infection with a GBS strain lacking β-h/c resulted in a marked reduction in expression of genes involved in the immune response, while the unencapsulated strain generally induced similar or greater expression levels for the same subset of genes. Cell-free bacterial supernatants containing β-h/c activity induced IL-8 release, identifying this toxin as a principal provocative factor for BBB activation. These findings were further substantiated in vitro and in vivo. Neutrophil migration across polar HBMEC monolayers was stimulated by GBS and its β-h/c through a process involving IL-8 and ICAM-1. In a murine model of hematogenous meningitis, mice infected with β-h/c mutants exhibited lower mortality and decreased brain bacterial counts compared with mice infected with the corresponding WT GBS strains.

Authors

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

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Figure 2

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Changes in HBMEC chemokine and cytokine secretion after infection with W...
Changes in HBMEC chemokine and cytokine secretion after infection with WT, β-h/c–deficient, or capsule-deficient GBS. Cell culture supernatants were assayed after 4 hours of incubation with GBS. Assays were performed for IL-8 (a), Groα (b), IL-6 (c), and GM-CSF (d). Representative data from duplicate experiments are shown. Error bars represent the 95% confidence interval of the mean of six wells. Error bars that are not visible represent an SD of less than ± 1.5. *P < 0.05 compared with WT. **P < 0.001 compared with WT.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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