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
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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Research Article Infectious disease

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

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.

Authors

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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Figure 3

Bacterial adhesins binding to cerebral endothelial LR in vivo.

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Bacterial adhesins binding to cerebral endothelial LR in vivo. (A) Crani...
(A) Cranial window image (original magnification, ×4) 10 minutes after intravascular injection of a mouse with fluorescent beads bearing CbpA, PilQ, PorA, or control pneumococcal protein Grr (intracellular response regulator). Images are representative of 10 mice per group, each imaged over 6 hours. (B) Quantitation of binding of fluorescent beads bearing CbpA or BSA (control) to mouse cerebral endothelium (beads/×40 field) as shown in A. Mice (1 symbol per animal; combined from 3 experiments; bars are the mean of the group) were injected i.v. with saline or TNF-α 1 hour prior to beads. *P < 0.01 versus BSA beads; 1-way ANOVA. (C) A comparison, similar to that in B, of the binding of CbpA beads in wild-type versus Pafr-null mice (NS, Student’s t test). (D) As in A, mice were pretreated with antibody against LR or control antiserum followed by infusion of CbpA beads. Images at 10 minutes after infusion are shown; images are representative of 3 mice per group.