Life-threatening infections in immunocompromised individuals represent a major and increasing problem worldwide, including the United States. Large numbers of people with potentially treatable underlying disease succumb to """"""""opportunistic"""""""" pathogens before the original illness can be controlled. This occurs because many """"""""opportunistic"""""""" pathogens are difficult to recognize and diagnose; and once identified, they often do not respond well to therapy. Nocardia asteroides, as normal inhabitant of the soil, is one of these important opportunistic pathogens that frequently causes serious pulmonary and systemic infections in compromised patients (including those that have AIDS). The mechanisms controlling nocardial pathogenesis is not completely understood. Our studies suggest that most of the virulence of N. asteroides results from a variety of substances both secreted into the environment and associated with the bacterial cell envelope. These compounds are important in: adherence and selective growth of the bacteria within the host; altering phagocyte function by inhibiting phagosome-lysosome fusion; blocking phagosomal acidification, and altering lysosomal enzyme activity; neutralization of bactericidal oxidative metabolites produced by phagocytes; toxicity towards host cells; and the ability of the organism to function as a facultative intracellular pathogen. Cellular components of N. asteroides will be fractioned by standard biochemical procedures. By utilizing a combination of high performance chromatography-mass spectroscopy (HPLC-MS) and monoclonal antibodies, specific fractions will be purified and characterized. Chemically defined compounds will be incorporated into liposome carriers or monoclonal antibodies will be combined to bacteria that contain these substances, and then their ability to modulate phagocyte activity will be quantitated in vitro, by using a computerized cytospectrophotometer. Mutants deficient in these properties will also be studied. By combining these methods in vitro and in vivo, the specific compounds involved in each aspect of nocardial pathogenesis will be determined. The results of these studies will provide a better understanding of the interactions of Nocardia in the brain and clarify their role in potentiating CNS symptomology. Furthermore, they will lay a foundation that will permit immunoprophylactic and immunotherapeutic augmentation of host resistance in immunocompromised hosts.
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