Pneumocystis carinii (PC) pneumonia is a serious pulmonary infection in immunocompromised patients both with and without the acquired immunodeficiency syndrome. Despite recent improvements in the prophylaxis and treatment of PC pneumonia, it remains a leading cause of morbidity and mortality in this population. Although microbiologic aspects of the PC organism have been well studied, relatively little is known regarding the pathogenesis of PC pneumonia. Ultrastructural studies have demonstrated that PC organisms attach tightly to the alveolar epithelium with a marked preference for binding to alveolar type I cells, however the basis for this binding preference and the mechanisms of PC attachment to type I cells remain unclear. The principal investigator has previously demonstrated that PC binds to the extracellular matrix protein fibronectin (Fn) and that Fn is necessary for optimal attachment of PC to a lung epithelial cell line in vitro. The focus of the current proposal is to extend these previous studies to determine the role of Fn in mediating PC attachment to alveolar type I cells in vitro. Preliminary data using in vitro differentiated rat derived type Il cells as a model for type I cells supports our hypothesis that PC not only attaches to type I cells in a Fn- dependent manner but that this attachment leads to an increase in the expression of Fn receptors on the surface of type I cells, thus increasing the number of potential PC binding sites. To further address this hypothesis, the specific aims of this proposal are to l) quantify binding of PC to isolated type II alveolar epithelial cells as a function of time as the cells differentiate in vitro; 2) determine whether PC attachment to in vitro differentiated type II cells is mediated by Fn and, identify the cell surface Fn receptors which mediate PC attachment; 3) determine the effect of PC attachment to differentiated type II cells on the expression of Fn receptors by type II cells; 4) determine the effect of the pneumocystis Fn-binding protein gpl2O on the expression of Fn receptors by differentiated type II cells; and 5) compare expression of PC binding alveolar epithelial Fn receptors in vitro with in vivo alveolar epithelial Fn receptor expression in the rat model of PC pneumonia. Our long term goal is to improve understanding of the pathogenesis of PC pneumonia by examining the role of host specific factors in the development of PC infection. These studies may provide novel targets for the development of innovative therapies for the prevention and treatment of PC infection.
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