Pneumococcal meningitis is a devastating infection of young children and older adults. For unknown reasons, despite the development of more highly bactericidal antibiotics, the high rates of mortality (up to 30%) and morbidity (almost 50%) of this infection have remained stable since the 1940's (6-8). It has thus become important to investigate alternative modes of intervention in the disease in order to achieve a substantial beneficial health impact. The need for new therapeutic strategies is accentuated by the overwhelming presentation of pneumococcal disease in AIDS patients and the emergence of new bacterial phenotypes in these patients (5). The pathogenesis of meningeal inflammation is still largely undefined. However, since a large inflammatory mass correlates with poor outcome of disease, modulation of inflammation is very likely to be of major importance in efforts to interrupt sequelae and lethality. A significant contribution to the understanding of the mechanism of meningeal inflammation, blood brain barrier injury and neuronal damage resulted from our determination that pneumococcal cell wall is a virtual library of multifaceted bioactive determinants each of potency approaching, or even exceeding, endotoxin or muramyl dipeptide (1,2,36). Unique to this proposal is a new technical ability to resolve and purify over 20 bioactive determinants from the heteropolymeric pneumococcal cell wall (15). Using these wall subcomponents as tools, this proposal seeks to determine the structure/activity relationships governing how Gram positive cell wall subcomponents interact with inflammatory cascades to induce diverse meningeal pathology. Leukocyte, vascular endothelial and meningeal endothelial interactions with walls will be identified as will mediator release triggered by these interactions. The biology of cell wall fragments generated during beta lactam therapy will be clarified. Since down-modulation of inflammation induced by cell wall enhances survival (9,10), this proposal has the potential to define anti-inflammatory activities important to new therapeutic agents for bacterial meningitis, and potentially other body sites as well. This proposal addressed the development of 3 such modulators: antibacterial antibodies preventing release of or host binding of inflammatory bacterial surface components; anti- leukocyte antibodies preventing adhesion and egress of leukocytes across the blood brain barrier; and nonsteroidal anti-inflammatory drugs.
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