Pneumocystis carinii (PC), an obligate extracellular pathogen, is a major cause of opportunistic infection in the lung. PC pneumonia develops in up to 80% of patients with acquired immune deficiency syndrome (AIDS) and is the major identifiable cause of death in 1/3 of patients with AIDS. Three key features of PC pneumonia include: 1) PC is an extracellular pathogen which selectively binds to Type I alveolar epithelial cells, 2) PC organisms are intimately associated with surfactant during attachment to the alveolar epithelium and 3) as PC pneumonia develops, PC eventually detach from the alveolar epithelial surface and epithelial cell injury becomes evident. However, mechanisms underlying the interaction of PC with alveolar epithelial cells are poorly understood. To address possible mechanisms, we have hypothesized: gp120 on the surface of PC mediates attachment to alveolar epithelial cells by a fibronectin- and/or surfactant protein A-dependent mechanism which ultimately results in protease-mediated detachment of PC from the epithelial cell. Using an in vitro model system developed in our laboratory, we propose to examine the following Specific Aims: 1) to determine if gp120 is a fibronectin (Fn)-binding glycoprotein with structural homology to known integrins, 2) to determine if gp120 binding to Fn mediates attachment to alveolar epithelial cells, 3) to determine if gp120 binds surfactant protein A (SPA) by a mannose-dependent mechanism, 4) to determine if PC binding to SPA mediates attachment to alveolar epithelial cells, 5) to determine if PC possess proteases capable of mediating detachment from alveolar epithelial cells. We speculate that PC-derived proteases may inadvertently damage target epithelial cells and possibly facilitate detachment of the epithelial cell from the basal lamina. We believe that our approach to examining PC infection is fundamentally different from prior work in the field and should result in the development of new and important information regarding specific mechanisms operative in PC pneumonia. If successful, these studies may potentially suggest novel therapeutic strategies for this devastating opportunistic lung infection.
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