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Blood-brain barrier invasion by group B Streptococcus depends upon proper cell-surface anchoring of lipoteichoic acid
Open accessAbstract
Group B streptococci (GBSs) are the leading cause of neonatal meningitis. GBSs enter the CNS by penetrating the blood-brain barrier (BBB), which consists of specialized human brain microvascular endothelial cells (hBMECs). To identify GBS factors required for BBB penetration, we generated random mutant libraries of a virulent strain and screened for loss of hBMEC invasion in vitro. Two independent hypo-invasive mutants possessed disruptions in the same gene, invasion associated gene (iagA), which encodes a glycosyltransferase homolog. Allelic replacement of iagA in the GBS chromosome produced a 4-fold decrease in hBMEC invasiveness. Mice challenged with the GBS DeltaiagA mutant developed bacteremia comparably to WT mice, yet mortality was significantly lower (20% vs. 90%), as was the incidence of meningitis. The glycolipid diglucosyldiacylglycerol, a cell membrane anchor for lipoteichoic acid (LTA) and predicted product of the IagA glycosyltransferase, was absent in the DeltaiagA mutant, which consequently shed LTA into the media. Attenuation of virulence of the DeltaiagA mutant was found to be independent of TLR2-mediated signaling, but bacterial supernatants from the DeltaiagA mutant containing released LTA inhibited hBMEC invasion by WT GBS. Our data suggest that LTA expression on the GBS surface plays a role in bacterial interaction with BBB endothelium and the pathogenesis of neonatal meningitis.
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“As TLR2 contributes to the pathogenesis of GBS meningitis (5) and downstream signaling of TLRs activate the MAPK pathway, we hypothesized that treatment of hBMECs with the TLR2 agonist Pam3CSK4 (P3C) would induce SNAI1 in hBMECs.”
From Bacterial induction of Snail1 contributes to blood-brain barrier disruption (2015) · cites this paper as [5]
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Metadata
- Authors
- Doran, K. S., Engelson, E. J., Khosravi, A., Maisey, H. C., Fedtke, I., Equils, O., Michelsen, K. S., Arditi, M., Peschel, A., & Nizet, V.
- Affiliations
- University of California San Diego (US)
- University of Tübingen (DE)
- Cedars-Sinai Medical Center (US)
- Corresponding author
- Doran, Kelly S.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2005-09-01
- Volume
- 115
- Issue
- 9
- Pages
- 2499-2507
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1193870
- OpenAlex
- W2127690345
- Cited by
- 231
- References
- 63
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 16 · 2023: 5 · 2022: 8 · 2021: 9 · 2020: 7 · 2019: 13 · 2018: 9 · 2017: 9 · 2016: 12 · 2015: 9 · 2014: 14 · 2013: 6 · 2012: 16
- FWCI
- 10.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health (5r03hd037224-02)
- University of California, San Diego
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-37224)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and Maternal Infections
- Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- Streptococcus agalactiae, lipoteichoic acid, IAGA, glycosyltransferases, cell surface anchoring, human brain microvascular endothelial cells, neonatal meningitis, bacterial virulence, bacteremia
- MeSH terms
- Animals, Biological Transport, Blood-Brain Barrier, Brain, Cell Membrane, Endothelium, Vascular, Glycolipids, Humans, Infant, Newborn, Lipopolysaccharides, Mice, Inbred C57BL, Streptococcus agalactiae, Teichoic Acids, Meningitis, Bacterial, Endothelial Cells, Mice
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