Mycobacterium tuberculosis (MTB) organisms are known to attach to alveolar macrophages, to undergo phagocytosis and to survive and to replicate within the intracellular environment of the macrophage. The establishment of infection or the destruction of the invading microorganisms is likely determined within the first few days of the initial exposure; and yet, this initial response of the host (prior to the development of a specific immune response) is not well understood. The focus of this proposal is to understand the mechanisms of MTB interaction with alveolar macrophages. Hypothesis to be tested in this proposal is MTB organisms use surfactant apoproteins and/or adhesive proteins to promote the recruitment of attachment to, and phagocytosis by alveolar macrophages in a manner which permits continued survival of the microorganism. This hypothesis will be studied by investigating 5 Specific Aims: 1) To determine the mechanisms of alveolar macrophage chemotaxis to MTB organisms; 2) To determine mechanisms of MTB adherence to alveolar macrophages via adhesive proteins such as fibronectin or vitronectin; 3) To determine the mechanism of MTB adherence to surfactant (and subsequently alveolar macrophages) via surfactant apoproteins such as SP-A or SP-D; 4) To determine which mechanisms of MTB adherence (or phagocytosis) trigger the macrophage cytotoxic response O2-derived radical response or reactive nitrogen intermediate generation) and which do not; 5) To determine how human bronchoalveolar lavage fluids from normal and HIV-infected individuals influence macrophage chemotaxis, MTB adherence, phagocytosis and the triggering of the macrophage cytotoxic response. If successful, these studies should result in new and important information regarding the pathogenesis of pulmonary tuberculosis, and possibly, the risk of tuberculosis in HIV-infected individuals.
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