Although the Mycobacterium avium complex represents a clinically significant group of opportunistic pathogens in AIDS patients, the lack of information regarding their pathogenicity has generated a critical scientific void that makes it difficult to treat infections involving these organisms. Recent investigations have suggested that the M. avium complex, or products derived from the organisms, can somehow modify or suppress immunological functions important in the host response. Because the serovar specific glycopeptidolipid antigens (GPL) represent a common feature among M. avium serovars, they have been the focus of research in this laboratory for the last several years. The GPL have successfully been internally radiolabeled and used to investigate postphagocytic events associated with these components. Recently, we have shown that the major lipopeptide fragment of the GPL (beta-lipid), obtained by beta- elimination of the oligosaccharide determinant, is immunosuppressive to mitogen-induced lymphoproliferative response of mouse splenic lymphocytes. Ultrastructural analysis by electron microscopy indicates that the beta-lipid influences this immunosuppression by initial interaction with splenic monocytes/macrophage, that in turn leads to an internal disruption of cellular organization and possible modification of macrophage function. Because we have recently observed GPL degradation in mouse and human monocytes, we will continue to examine GPL degradation in an attempt to identify specific metabolic components that are immunosuppressive. Individual cell fractions will be assayed to identify specific cells that are affected by both GPL and beta-lipid. In addition, other M. avium lipopeptides, similar in structure to the beta-lipid, will be examined for their immunosuppressive properties.
Specific aims are: 1) to purify radiolabeled and nonradiolabeled lipids, 2) to investigate the degradation of GPL, 3) to examine the affect of the beta-lipid and GPL on mononuclear cells, and 4) to examine the effect of related lipopeptides on mononuclear cell responses. By defining the role of individual immunosuppressive M. avium lipids, we hope to obtain a composite analysis that can eventually be used to more clearly define mycobacterial pathogenesis.
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