Group B streptococcal β-hemolysin/cytolysin activates neutrophil signaling pathways in brain endothelium and contributes to development of meningitis
Open accessAbstract
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 beta-hemolysin/cytolysin toxin (beta-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, Groalpha, Grobeta, 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 beta-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 beta-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 beta-h/c through a process involving IL-8 and ICAM-1. In a murine model of hematogenous meningitis, mice infected with beta-h/c mutants exhibited lower mortality and decreased brain bacterial counts compared with mice infected with the corresponding WT GBS strains.
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Δiag mutant lacks ability to properly anchor LTA.
“We have previously described a GBS mutant (Δiag) that lacks the ability to properly anchor (LTA) (6), a known TLR2 ligand (30).”
From Bacterial induction of Snail1 contributes to blood-brain barrier disruption (2015) · cites this paper as [6]
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- Authors
- Doran, K. S., Liu, G. Y., & Nizet, V.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Doran, Kelly S.
- Venue
- Journal of Clinical Investigation
- Published
- 2003-09-01
- Volume
- 112
- Issue
- 5
- Pages
- 736-744
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC182187
- OpenAlex
- W2146811846
- Cited by
- 262
- References
- 39
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 29 · 2023: 9 · 2022: 14 · 2021: 11 · 2020: 12 · 2019: 8 · 2018: 10 · 2017: 13 · 2016: 14 · 2015: 12 · 2014: 17 · 2013: 9 · 2012: 9
- FWCI
- 7.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r03hd037224-02)
- National Institute of Allergy and Infectious Diseases (AI3614-05)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-37224)
- Topics
- Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Neonatal and Maternal Infections
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- Streptococcus agalactiae, meningitis, blood-brain barrier, brain microvascular endothelial cells, neutrophil recruitment, neutrophil activation, interleukin-8, ICAM-1, bacterial virulence factors, endothelial gene expression, neutrophil migration
- MeSH terms
- Bacterial Proteins, Blood-Brain Barrier, Brain, Cell Movement, Disease Models, Animal, Endothelium, Vascular, Enzyme-Linked Immunosorbent Assay, Hemolysin Proteins, Humans, Neutrophils, Streptococcus agalactiae, Signal Transduction, Interleukin-8, Meningitis, Bacterial, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling
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