Pneumocystis pneumonia induces caspase-9 mediated apoptosis in alveolar macrophages

Pneumocystis pneumonia is a life threatening illness in severely immunocompromised patients. Fifty-five years after the first reported case of pneumocystosis in humans, the pathology associated with the disease still remains largely unknown. One area of great interest is the alveolar macrophage and its role in host protection against Pneumocystis (Pc) infections. During infection, there is a decrease in alveolar macrophage number. From studies conducted by Lasbury et al., it is clear that the decrease in alveolar macrophages was partly caused by apoptosis, and a specific caspase-9 inhibitor could prevent this apoptosis (Lasbury et al., 2006). The mechanism of apoptosis induction was unknown, so studies were conducted to determine the apoptosic mechanisms, upstream kinases that may influence apoptosis, and the factors that induce apoptosis. Results indicated that Pc infection led to caspase-9 mediated apoptosis. In addition, polyamines found in high concentrations in the lung of Pc infected animals induced apoptosis, generated reactive oxygen species, and altered survival kinases of normal alveolar macrophages. An ion exchange method for depletion of polyamines from biological fluids was applied during these studies and confirmed the role of polyamines in Pc-mediated alveolar macrophage apoptosis. Results of this study also revealed that Pneumocystis infection led to an increase in total TGF-beta1 protein, but a decrease in the activated fraction of this cytokine and subsequently less Smad signaling. There was also a decrease in PI3K and Akt activation in alveolar macrophages during Pcp. These results along with the decrease in activated TGF-beta1 suggest that Pcp lowers the alveolar macrophage ability to resist the polyamine-mediated apoptosis.