Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models

Carlos J. Orihuela, Jafar Mahdavi, Justin Thornton, Beth Mann, Karl G. Wooldridge, Noha Abouseada, Neil J. Oldfield, Tim Self, Dlawer A.A. Ala'Aldeen, Elaine I. Tuomanen

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172 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1638-1646
Number of pages9
JournalJournal of Clinical Investigation
Volume119
Issue number6
DOIs
StatePublished - Jun 1 2009

ASJC Scopus subject areas

  • Medicine(all)

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    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. (2009). Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models. Journal of Clinical Investigation, 119(6), 1638-1646. https://doi.org/10.1172/JCI36759