The laminin receptor protein as a target for therapeutics against bacterial meningitis
Lead Research Organisation:
University of Nottingham
Department Name: School of Molecular Medical Sciences
Abstract
Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae are the most common causes of bacterial meningitis worldwide. Although these bacteria are sensitive to most antibiotics in current use, and vaccines are available against some strains of these bacteria, they continue to cause high morbidity and mortality in all age groups. Better understanding of the disease process is required before novel preventative and treatment strategies are designed. In recent studies, we identified a key human molecule (laminin receptor, LR) that is involved in mediating bacterial invasion of the blood-brain barrier. We identified LR-binding molecules on each of the three bacterial pathogens and carried out extensive experiments confirming the specificity of the interactions. In this proposal, we plan to study molecular and biological properties of the interaction with the ultimate goal of exploiting the LR-bacterial interaction to develop therapeutic and/or preventative agents that can block bacterial invasion of the blood brain barrier.
Technical Summary
Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae are the leading bacterial pathogens responsible for pyogenic meningitis and other sepsis syndromes. Despite sensitivity to antibiotics and availability of vaccines against a subset of these bacteria, they remain the major causes of morbidity and mortality worldwide. Better understanding of the host-pathogen interaction at the blood-brain barrier (BBB) is key to the design of novel therapeutic and
preventative strategies. Given the convergent evolution of these
bacteria, we hypothesized that a common molecular interaction might underlie their tropism for the BBB. Using several independent methods, we identified the 37/67-kD laminin receptor (LR) as a common receptor for all three bacteria on host brain vascular endothelial cells. Mutagenesis studies indicated the corresponding LR binding adhesins were pneumococcal CbpA, meningococcal PilQ and PorA, and OmpP2 of H. influenzae. Competitive binding of the bacteria, purified adhesins, LR peptides and antibodies suggested a common LR-carboxyterminal recognition site. The main objectives of this proposal are (i) localising the minimum functional domains on both the LR protein and the LR-binding bacterial adhesins, (ii) elucidating the in vitro and in vivo functional relevance of the identified LR-adhesin interactions, and (iii) understanding LR-mediated early cell signalling events in host cells in response to bacterial ligands, and determining the impact of inhibiting the LR-adhesin interaction and bacterial-host cell interaction. The ultimate goal is to develop therapeutic and/or preventative agents that can block the LR-bacterial adhesin binding domains.
preventative strategies. Given the convergent evolution of these
bacteria, we hypothesized that a common molecular interaction might underlie their tropism for the BBB. Using several independent methods, we identified the 37/67-kD laminin receptor (LR) as a common receptor for all three bacteria on host brain vascular endothelial cells. Mutagenesis studies indicated the corresponding LR binding adhesins were pneumococcal CbpA, meningococcal PilQ and PorA, and OmpP2 of H. influenzae. Competitive binding of the bacteria, purified adhesins, LR peptides and antibodies suggested a common LR-carboxyterminal recognition site. The main objectives of this proposal are (i) localising the minimum functional domains on both the LR protein and the LR-binding bacterial adhesins, (ii) elucidating the in vitro and in vivo functional relevance of the identified LR-adhesin interactions, and (iii) understanding LR-mediated early cell signalling events in host cells in response to bacterial ligands, and determining the impact of inhibiting the LR-adhesin interaction and bacterial-host cell interaction. The ultimate goal is to develop therapeutic and/or preventative agents that can block the LR-bacterial adhesin binding domains.