Emerging molecular targets in the treatment of bacterial meningitis.
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.
Kim
Kwang Sik
KS
Pediatric Infectious Diseases Division, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Park 256, Baltimore, MD 21287, USA. kwangkim@jhmi.edu
D051722:ADAM Proteins / Q000037:antagonists & inhibitors; D000072198:ADAM17 Protein; D000328:Adult; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016470:Bacteremia / Q000150:complications; D001428:Bacterial Vaccines; D001812:Blood-Brain Barrier; D020169:Caspases / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D015195:Drug Design; D004730:Endothelium, Vascular / Q000502:physiology; D018846:Excitatory Amino Acids / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D007116:Immunization, Passive; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D061965:Matrix Metalloproteinase Inhibitors; D016920:Meningitis, Bacterial / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D009474:Neurons / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000900:Anti-Bacterial Agents; D001428:Bacterial Vaccines; D018846:Excitatory Amino Acids; D036341:Intercellular Signaling Peptides and Proteins; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D011480:Protease Inhibitors; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D020169:Caspases; D051722:ADAM Proteins; D000072198:ADAM17 Protein