Emerging molecular targets in the treatment of bacterial meningitis

Abstract

The mortality and morbidity associated with bacterial meningitis have remained significant despite advances in antimicrobial chemotherapy and supportive care. A major contributing factor to this high mortality and morbidity is our incomplete understanding of the pathogenesis of this disease and its associated neurological sequelae. Most cases of bacterial meningitis develop as a result of haematogenous spread, but it is unclear how circulating bacteria cross the blood–brain barrier. Experimental animal studies indicate that two forms of neuronal injury, such as necrotic cortical injury and apoptotic hippocampal injury, are predominant in bacterial meningitis, but the mechanisms by which these two forms of injury occur are unclear. Recent studies have identified several bacteria–host determinants for bacterial translocation of the blood–brain barrier, and several host inflammatory markers that are associated with neuronal injury in animal models of experimental bacterial meningitis. These determinants/markers may provide important targets for the prevention and treatment of bacterial meningitis. This review focuses on representative steps in the pathogenesis of bacterial meningitis that are likely to be key targets in coming years, and summarises the status of current knowledge for each target.

• bacteraemia
• bloodbrain barrier
• brain microvascular endothelial cells
• calcitonin generelated peptide
• caspases
• chemokines
• CNS
• cytokines
• cytosolic phospholipase A₂ (cPLA₂)
• cytotoxic necrotising factor-1 (CNF-1)
• E. coli K1
• endothelins
• excitatory amino acids
• focal adhesion kinase
• gp96
• Group B streptococcus
• Ibe
• laminin receptor precursor
• Listeria
• monocytogenes
• matrix metalloproteinases
• meningitis
• Neisseria meningitidis
• NF-κB
• OmpA
• peroxynitrite
• phosphatidylinositol 3-kinase (PI3K)
• reactive nitrogen species
• reactive oxygen species
• Rho GTPases
• Streptococcus pneumoniae
• substance P
• TNF-α-converting enzyme