Our laboratory is principally concerned with understanding the pathogenesis of Pneumocystis carinii pneumonia and other infections of the immune compromised host. P. carinii pneumonia is a common and frequently lethal complication of immune suppression affecting patients with AIDS, malignancy, organ transplantation and underlying inflammatory diseases. Host responses to P. carinii are not fully defined, but center around the alveolar macrophage, which acts to recognize and clear the organism from the lung. Over the past several years our laboratory has investigated mechanisms by which macrophages recognize and respond to P. carinii. Following interaction with P. carinii, macrophages act to phagocytize and degrade the organism. In addition, they are stimulated to release a number of inflammatory mediators, most notably tumor necrosis factor-a and eicosanoid metabolites - predominantly PGE2. While host inflammatory responses are essential to elimination of infection, they contribute significantly to lung injury and respiratory failure. Data from our laboratory suggests that respiratory failure and death in pneumonia is correlated more with the release of inflammatory products than with the organisms burden in the lung.
Our recent studies have centered on the role of the macrophage mannose and beta-glucan receptor systems in mediating phagocytosis and cytokine release in this infection. Our work demonstrates that while the macrophage mannose receptor is the principal mediator of organism phagocytosis, it does not mediate release of TNFa in response to P. carinii. Instead, macrophage TNFa response during infection appears to be largely transduced through the beta-glucan receptor pathway. We have recently purified a 120 kDa P. carinii glycoprotein termed gpA which appears to act as the principal microbial ligand for alveolar macrophage mannose receptors. Efforts are underway to isolate P. carinii components interacting the beta-glucan receptors. Additional studies are underway evaluating the roles of alveolar adhesive proteins including vitronectin, fibronectin, and surfactant components as candidate non-immune opsonins which modulate interaction of P. carinii with the macrophage during infection.