Pneumocystis carinii pneumonia is a major cause of mortality in immunosuppressed subjects with and without the acquired immune deficiency syndrome (AIDS). Although much has been learned in recent years regarding the microbiologic aspects of P. carinii, the mechanisms underlying P. carinii pneumonia are poorly understood. For example, prior ultrastructural studies suggest the successful attachment of P. carinii to target lung cells is critical to the growth of the organisms and the development of pneumonia; yet, the biochemical mechanisms of attachment of P. carinii are virtually unstudied. Furthermore, alveolar epithelial cell damage in P. carinii pneumonia is well recognized, but no studies have yet attempted to examine the mechanism of this adverse effect. The normal host response to invading microorganisms is the development of an inflammatory or immune response within the lung. In contrast, P. carinii pneumonia in immunosuppressed animals or human subjects is generally characterized by a poor but variable inflammatory response. The ability of P. carinii (via cell attachment) to directly induce lung cells to release proinflammatory mediators is unstudied, and may provide important insight into the mechanisms of the pneumonia and the host response to the organism. We propose an entirely different approach to the study of P. carinii pneumonia with a focus on the in vitro interaction of P. carinii with cultured lung cells as a model of P. carinii pneumonia. We propose the following Specific Aims: 1) to determine the mechanism(s) of attachment of P. carinii to target lung cells, 2) to determine if P. carinii adversely affects lung cell function, 3) to determine if P. carinii induces target lung cells to generate proinflammatory mediators, 4) to determine if proinflammatory mediators or inflammatory cells inhibit P. carinii viability or growth and 5) to determine if a """"""""cause-effect"""""""" relationship exists between P. carinii attachment and impairment of lung cell function or release of proinflammatory mediators. Such studies will likely provide new insight into P. carinii pneumonia and potentially suggest novel therapeutic strategies for this devastating lung disorder.
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