Cited by 232Neonatal and Maternal InfectionsBacterial Infections and VaccinesBarrier Structure and Function Studies

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Blood-brain barrier invasion by group B Streptococcus depends upon proper cell-surface anchoring of lipoteichoic acid

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Doran, Kelly S., Engelson, Erin J., Khosravi, Arya, Maisey, Heather C., Fedtke, Iris, Equils, Ozlem, Michelsen, Kathrin S., Arditi, Moshe, Peschel, Andreas, Nizet, Victor·2005·Journal of Clinical Investigation

DOI 10.1172/jci23829PMC PMC1193870

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Abstract

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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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: Doran, Kelly S.
Khosravi, Arya
Equils, Ozlem
Michelsen, Kathrin S.
Arditi, Moshe
Peschel, Andreas
Nizet, Victor
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2005-09-01
Volume: 115
Issue: 9
Pages: 2499-2507
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci23829
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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Blood-brain barrier invasion by group B Streptococcus depends upon proper cell-surface anchoring of lipoteichoic acid

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