Macrophage signaling upon M avium infection

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DESCRIPTION (provided by applicant): Mycobacterium avium is a major opportunistic pathogen in AIDS patients and a significant cause of increased morbidity and mortality in HIV infected individuals. M. avium is an intra-macrophage pathogen which requires attachment and invasion of its host cell to initiate disease. However, macrophages also play an essential role in controlling a M. avium infection. Therefore, a key aspect to the understanding of M. avium pathogenesis is to define the macrophage response to the mycobacteria and how the bacilli modulates this response to limit the macrophage's ability to control the infection. We have initiated studies to define the macrophage signaling pathways activated during a M. avium infection and how this differs between M. avium strains of varied pathogenicity and between pathogenic and non-pathogenic mycobacteria. The activation of these signaling pathways are necessary for the production of cytokines, chemokines and other effector molecules required to control a mycobacterial infection. Our studies have shown that macrophages infected with pathogenic M. avium show limited activation of the mitogen activated protein kinases (MAPK), cyclic AMP and other signaling molecules relative to cells infected with non-pathogenic mycobacteria. The consequence of this tempered signaling response is limited production of TNF-alpha, IL-1 beta and nitric oxide synthase by the M. avium infected macrophages. Therefore, we hypothesize that M. avium has evolved mechanisms to minimize the activation of the MAPK and other signaling molecules and that this ability is an important aspect of its pathogenicity. The glycopeptidolipids (GPL) are one well-characterized component of the M. avium cell wall and our recent data indicate that macrophages infected with a M. avium 2151 morphotype which lacks GPLs has prolonged MAPK activation compared to cells infected with a 2151 morphotype containing GPLs. Therefore we propose to: 1) Define the mechanism by which M. avium limits MAPK activation in infected macrophages 2) Determine the importance of GPLs in M. avium pathogenesis and in macrophage activation. We will use a combination of genetic, immunological and cell biological approaches to address these important questions.