Bacterial meningitis is an inflammatory disease of the meninges that enclose the brain and spinal cord and is associated with significant morbidity and mortality. Disease complications include brain damage, hearing loss, learning disabilities, seizures, and motor handicaps. The host inflammatory response to the pathogen, rather than the pathogen itself, is largely responsible for the damage that results from bacterial meningitis. The host inflammatory innate immune response is initiated by activation of intracellular pro-inflammatory signaling pathways. The TLR/IL-1R signaling pathway, which is activated by the interaction of bacterial components with host Toll-like receptors (TLRs) or by the pro-inflammatory cytokine IL-1, results in production of pro- inflammatory cytokines, chemokines, enhanced expression of cell-adhesion molecules, and production of reactive oxygen species and reactive nitrogen intermediates. In bacterial meningitis, these inflammatory mediators cause the breakdown of the blood-brain barrier and formation of brain edema, leading to clinical disease development. Corticosteroids, given before or concomitantly with antibiotics, are the only anti- inflammatory therapy that have shown efficacy in humans. New treatment strategies that selectively target the host inflammatory innate immune response in bacterial meningitis are needed. We have recently identified and characterized a peptide, derived from the A52R vaccinia virus protein, that i) inhibits the in vitro production of pro-inflammatory cytokines and chemokines in response to a variety of TLR ligands, ii) functions in vivo to significantly reduce bacterial-induced inflammation in a mouse model of middle ear inflammation, and iii) in preliminary in vitro studies reduces LPS-induced expression of the cell-adhesion molecule ICAM-1. We propose in this study to test the feasibility of this peptide as a new treatment to reduce inflammation and limit disease development in bacterial meningitis. Experiments will assess in vitro the effectiveness of the peptide to inhibit bacterial and cytokine-induced production of inflammatory mediators such as cytokines, chemokines, cell-adhesion molecules, and reactive nitrogen intermediates (specific aim #1). The proposal will then examine the effectiveness of the peptide in vivo to inhibit inflammation and limit disease development in a mouse model of experimental bacterial meningitis (specific aim #2). If successful, these studies will provide the basis for continued assessment of this peptide as a new treatment strategy to inhibit inflammation in bacterial meningitis. Mortality and morbidity rates remain high for bacterial meningitis, even with the use of antibiotics. New treatment approaches are needed to limit the inflammation seen in patients with meningitis. The current study will test a new anti-inflammatory treatment strategy for bacterial meningitis. ? ? ?
