Recent investigation has focused on serine proteinases mechanisms by which PC serine proteinases may contribute to the pathogenesis of PC pneumonia or will be explored. Pneumocystis carinii (PC) is a major cause of morbidity and mortality among immunocompromised patients. The pathogenesis of PC pneumonia remains poorly understood. Recent studies have focused on mechanisms of PC adherence to fibronectin on respiratory epithelium in the pathogenesis of PC pneumonia. Current concepts suggest that PC not only adhere but can detach from respiratory epithelium. The mechanisms of PC detachment and lung tissue injury are unknown. Recently our laboratory has identified and characterized a serine proteinase from PC with chymotrypsin-like (chymase) activity that may degrade the adhesive protein fibronectin. Serine proteinases are known to play a role in cell adhesion, migration, and injury. We hypothesize that PC chymase represents one mechanism by which the organism detaches from the alveolar epithelial surface and contributes to lung tissue injury.
Specific aims are proposed to: 1) Purify and characterize PC chymase. 2) Determine the catalytic site and substrate specificity of PC chymase. 3) Characterize PC chymase mediated fibronectin proteolysis. 4) Determine if PC chymase can mediate PC detachment. 5) Determine if PC chymase can mediate lung cell injury.
