Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models
Open accessAbstract
A diverse array of infectious agents, including prions and certain neurotropic viruses, bind to the laminin receptor (LR), and this determines tropism to the CNS. Bacterial meningitis in childhood is almost exclusively caused by the respiratory tract pathogens Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae, but the mechanism by which they initiate contact with the vascular endothelium of the blood brain barrier (BBB) is unknown. We hypothesized that an interaction with LR might underlie their CNS tropism. Using affinity chromatography, coimmunoprecipitation, retagging, and in vivo imaging approaches, we identified 37/67-kDa LR as a common receptor for all 3 bacteria on the surface of rodent and human brain microvascular endothelial cells. Mutagenesis studies indicated that the corresponding bacterial LR-binding adhesins were pneumococcal CbpA, meningococcal PilQ and PorA, and OmpP2 of H. influenzae. The results of competitive binding experiments suggest that a common adhesin recognition site is present in the carboxyl terminus of LR. Together, these findings suggest that disruption or modulation of the interaction of bacterial adhesins with LR might engender unexpectedly broad protection against bacterial meningitis and may provide a therapeutic target for the prevention and treatment of disease.
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Other meningeal pathogens bind ECM components and receptors to mediate bacterial-BBB interactions.
“Other meningeal pathogens, such as Streptococcus pneumoniae (SPN), E. coli K1, Neisseria meningitidis, and Haemophilus influenza type B (HiB, also bind ECM components and ECM receptors (e.g., integrins and laminin receptor) to mediate bacterial-BBB interactions (12)(13)(14)(15).”
From Bacterial induction of Snail1 contributes to blood-brain barrier disruption (2015) · cites this paper as [14]
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References 44 · Cited by 303
Research works printed but not linked: 1
- [3]Hilario E., et al. Presence of laminin and 67kDa laminin-receptor on endothelial surface of lung capillaries. Histol. Histopathol. 1996;11:915–918. [PubMed] [Google Scholar]
- Authors
- Orihuela, C. J., Mahdavi, J., Thornton, J., Mann, B., Wooldridge, K. G., Abouseada, N., Oldfield, N. J., Self, T., Ala’Aldeen, D. A. A., & Tuomanen, E. I.
- Affiliations
- St. Jude Children's Research Hospital (US)
- University of Nottingham (GB)
- Queen's Medical Centre (GB)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2009-06-01
- Volume
- 119
- Issue
- 6
- Pages
- 1638-1646
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2689107
- OpenAlex
- W1973339314
- Cited by
- 303
- References
- 44
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 19 · 2023: 14 · 2022: 16 · 2021: 18 · 2020: 19 · 2019: 21 · 2018: 19 · 2017: 16 · 2016: 9 · 2015: 22 · 2014: 18 · 2013: 26 · 2012: 25
- FWCI
- 22.17
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Repository@Nottingham (University of Nottingham) (submittedVersion)
- Funders
- National Cancer Institute (CA21765, P30CA021765)
- National Institute of Allergy and Infectious Diseases (R01AI27913, R01AI027913)
- Topics
- Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
- Keywords
- laminin receptor, blood-brain barrier, bacterial meningitis, Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, bacterial adhesins, CbpA, PilQ, PorA, brain microvascular endothelial cells, ligand-receptor interactions, therapeutic target
- MeSH terms
- Amino Acid Sequence, Animals, Bacterial Adhesion, Blood-Brain Barrier, Disease Models, Animal, Female, Haemophilus influenzae, Ligands, Models, Molecular, Neisseria meningitidis, Streptococcus pneumoniae, Meningitis, Bacterial, Protein Structure, Tertiary, Receptors, Laminin, Mice
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