Opportunistic pathogens in immunocompromised individuals represent a major and expanding public health problem. Nocardia asteroides is an important """"""""opportunistic pathogen"""""""" that frequently causes serious pulmonary and systemic disease in AIDS patients as well as a large variety of immunocompromising conditions. Also, these organisms cause life threatening infections (especially in the brain) in otherwise healthy persons. Recently, it was shown that Nocardia causes parkinson's-like disease in experimental animals which suggest a possible role for Nocardia in Parkinson's disease. Furthermore, a variety of other neurological signs are recognized in subclinically infected mice, suggesting a possible involvement of Nocardia in several types of neurodegenerative diseases. The mechanisms controlling nocardial pathogenesis are not understood. Studies show that most of the virulence of H. asteroides results from substances secreted into the environment or associated with the cell envelope. These compounds are important in: adherence and selective growth of the bacteria in the host; altering phagocyte function by inhibiting phagosome-lysosome fusion; blocking phagosomal acidification; altering lysosomal enzyme activity; neutralization of microbicidal activities of phagocytes; toxicity toward host cells; and the ability of Nocardia to grow in cells. The goals of this proposal are to: 1) elucidate the relationship of the structure of glycolipids to pathogenesis, especially in the brain; and 2) determine the mechanisms of nocardial interactions within specific regions of the brain. To achieve these goals, glycolipids will be purified by standard biochemical procedures combined with an HPLC-MS. Defined components will be incorporated into liposome carriers and their ability to modulate host cell activities will be quantitated. N. asteroides GUH-2 as well as specific mutants will be used, and their interactions within specific regions of the brain will be studied by EM, and by histochemical, cytochemical, immunologic and biochemical methodologies. This approach focused on interactions within the brain should define the specific roles of nocardial glycolipids in nocardial pathogenesis and lead to a better understanding of the complex interactions of nocardia within the brain that results in different neurodegenerative responses. A complete understanding of these interactions are essential and should result in better methods of diagnosis, treatment, management and prevention of life threatening diseases caused by Nocardia.
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