Despite recent advances in its diagnosis, therapy, and prophylaxis, Pneumocystis carinii pneumonia (PCP) remains a leading case of morbidity and mortality in patients with AIDS. This life-threatening opportunistic infection is associated with impaired gas exchange leading to clinically significant hypoxemia. The disease is caused by an enigmatic pathogen whose basic biology is poorly understood because of difficulty culturing the organism in vitro and cumbersome animal models of the infection. Surfactant abnormalities and pulmonary inflammation appear to have an important role in the pathogenesis of PCP and its associated hypoxemia; however the initiating and effector mechanisms for these events are not known. Because the hypoxic lung injury produced by P. carinii is associated with abnormalities in surfactant biophysics and lipid content, the investigators hypothesize that: 1. Severe disruption of normal pulmonary surfactant homeostasis is induced directly by P. carinii. The interaction of P. carinii with the distal alveolar epithelium is mediated by an abundant, immunogenic, cell-surface protein, glycoprotein A (gpA) found on the outer cell wall of the organism. These events include alteration in surfactant lipid metabolism and changes in the expression and cellular metabolism of surfactant specific proteins. 2 Additional indirect mechanisms mediated via TNF alpha produced by the host inflammatory response further disrupt surfactant homeostasis. The investigators propose to characterize the role of gpA in the specific interactions of this organism with host epithelial cells and to study mechanisms by which P. carinii mediates the severe lung injury seen with PCP using a murine model of infection.
The specific aims are: 1. Define the cellular effects of whole P. carinii and purified gpA on lung surfactant metabolism in vitro: 2. Characterize changes in surfactant metabolism in an immunocompromised mouse model of PCP. To accomplish these aims, they will utilize in vivo animal systems to grow P. carinii as a source of purified gpA and as a well-controlled model of PCP infection. The project will combine elements derived from several thematic research programs to yield a comprehensive investigative proposal including: 1. A Principal Investigator with expertise in the major aspects of surfactant biology; 2. A co-investigator experienced with P. carinii biology and gpA purification; 3. Consultants recognized as authorities on the scid mouse model of PCP and on isolated lung perfusion.
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