The pneumococcus remains the cause of meningitis with the greatest morbidity and mortality in children and older adults. This pattern persists despite the use of antibiotics of exceptionally rapid bactericidal activity. Over the first 5 years of this proposal we have sought to understand the biochemical basis of the inflammatory response to pneumococci in the subarachnoid space. We established that the pneumococcal cell wall is a library of inflammatory components which incite the cytokine, coagulation and arachidonate cascades and directly injure endothelial cells of the blood brain barrier. We then extended this concept to the peptidoglycan of H. influenzae showing it is also highly inflammatory in a pattern distinct from that of pneumococcal wall and endotoxin. Further, we established that the release of cell wall during antibiotic-induced death engenders a dramatic host response which is responsible for serious injury to the host tissues. This provided a rationale for design of agents which can act as partner drugs with antibiotics to selectively control the injurious components of the host defense response. The recent approval of the use of dexamethasone in this context by the American Academy of Pediatrics is a result of the extension of our animal model work to clinical trials by the National Cooperative Meningitis Study Group and confirms the benefits of our approach. Having determined that gram positive and negative disease have important differences in pathophysiology on the molecular level, such as in the cytokine profile and the participation of coagulation components such as platelet activating factor, we now seek to define agents which can impact on outcome by modulating common components of both classes of infection, particularly the leukocyte. Unique to this proposal is the ability to resolve the cell wall of pneumococcus and H. influenzae into over 15 bioactive determinants each. A detailed structure-activity relationship will now be sought for these cell wall glycopeptides vis a vis the ability to injure CNS tissues by activation of macrophages and endothelial cells. In particular, these glycopeptides induce blood brain barrier permeability and that activity will be used to open the blood brain barrier from the intravenous side with the aim of developing agents which can enhance the delivery of therapeutics to the CNS. The receptor(s) for cell wall on the cerebral capillary endothelium will be identified and the physiological response of the cell to ligation of the receptor will be determined, particularly as regards induction of cell separation and production of IL-1. Finally, agents which compete with normal leukocyte trafficking across the cerebral capillary endothelium by the integrin and selectin pathways will be identified. These agents will transiently block leukocyte recruitment and are predicted to surpass dexamethasone in selectivity, efficacy, safety and breadth of applicability in other infectious sites for the down modulation of damaging inflammation associated with antibiotic therapy.
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