Professor of Pathology and Laboratory Medicine
Telephone: (317) 274-2596
FAX: (317) 278-0643
email: chlee@iupui.edu

I study the pathogenesis of Pneumocystis carinii. During P. carinii infection, alveolar macrophages are defective in phagocytosis, and the number of alveolar macrophages is decreased. We found that the defect in phagocytosis is due to a reduced expression of the transcription factor GATA-2. Incubation of normal alveolar macrophages with the major surface glycoprotein (MSG) also causes these cells to become defective in phagocytosis and GATA-2 gene expression to be down regulated. Confocal microscopic studies show that the actin cytoskeleton in alveolar macrophages from P. carinii-infected hosts is aberrant, and DNA microarray studies reveal altered expression of many genes related to the actin cytoskeleton in alveolar macrophages during Pneumocystis infection. Based on these results, we hypothesize that Pneumocystis infection reduces the phagocytic ability of alveolar macrophages through the action of MSG on gene transcription, resulting in altered cytoskeletal gene expression and function. We are investigating the effect of P. carinii infection on the polymerization and depolymerization of the actin cytoskeleton and the mechanisms by which GATA-2 and P. carinii MSG cause abnormal actin assembly and defect in phagocytosis of alveolar macrophages.

 

We found three problems that may cause the decrease in alveolar macrophage number during P. carinii infection, including increased rate of apoptosis and emigration of alveolar macrophages and inability of recruited monocytes to differentiate to alveolar macrophages. Several caspases are found to be activated in alveolar macrophages from P. carinii-infected hosts. We hypothesize that suppression of the activity of activated caspases will prevent apoptosis of alveolar macrophages and thus inhibiting the proliferation of P. carinii in the lung. Several different caspase inhibitors have been tried, and the caspase 9 inhibitor was found to be effective in preventing P. carinii-infected rats from dying. We are investigating the possibility of producing less expensive caspase 9 inhibitor and developing a non-invasive method for drug delivery. We are also investigating how P. carinii causes alveolar macrophages to undergo apoptosis and to migrate out of the lung and monocytes unable to differentiate to alveolar macrophages.

Publications:

1. Lasbury ME. Durant PJ. Lee CH. Inducible nitric oxide synthase expression in Pneumocystis carinii pneumonia. Journal of Eukaryotic Microbiology. 50 Suppl:634-5, 2003.
2. Lasbury ME. Lin P. Tschang D. Durant PJ. Lee CH. Effect of bronchoalveolar lavage fluid from Pneumocystis carinii-infected hosts on phagocytic activity of alveolar macrophages. Infection & Immunity. 72(4):2140-7, 2004 Apr.
3. Lasbury ME. Tang X. Durant PJ. Lee CH. Effect of transcription factor GATA-2 on phagocytic activity of alveolar macrophages from Pneumocystis carinii-infected hosts.  Infection & Immunity. 71(9):4943-52, 2003 Sep.
4. Lee CH. Lasbury ME. Xuei X. Jerome RE. Edenberg HJ. Lu D. Durant PJ. Tschang D. Transcriptional changes in alveolar macrophages during Pneumocystis pneumonia.  Journal of Eukaryotic Microbiology. 50 Suppl:645, 2003.
5. Lasbury ME. Durant PJ. Lee CH. Transtracheal inoculation of Pneumocystis carinii in immunocompetent animals.  Journal of Eukaryotic Microbiology. 50 Suppl:643-4, 2003.
6. Lasbury ME. Lin PM. Tschang D. Durant PJ. Lee CH. Pneumocystis carinii factor responsible for reduced phagocytic activity in alveolar macrophages.  Journal of Eukaryotic Microbiology. 50 Suppl:641-2, 2003.
7. Lasbury ME. Durant PJ. Lee CH. Pneumocystis carinii cyst is associated with inflammation in the host.  Journal of Eukaryotic Microbiology. 50 Suppl:639-40, 2003.
8. Lasbury ME. Durant PJ. Lee CH. Numbers of alveolar macrophages are increased during Pneumocystis pneumonia in mice. Journal of Eukaryotic Microbiology. 50 Suppl:637-8, 2003.
9. Lasbury ME. Durant PJ. Lee CH. Life cycle stage-specific and encystment protein profiles in Pneumocystis carinii.  Journal of Eukaryotic Microbiology. 50 Suppl:636, 2003.
10. Lasbury ME. Durant PJ. Lee CH. Environmental stress and encystment of Pneumocystis carinii.  Journal of Eukaryotic Microbiology. 50 Suppl:632-3, 2003.
11. Lasbury ME. Durant PJ. Lee CH. Decrease in alveolar macrophage number during Pneumocystis carinii infection.  Journal of Eukaryotic Microbiology. 50 Suppl:630-1, 2003.
12. Lasbury ME. Durant PJ. Bartlett MS. Smith JW. Lee CH. Correlation of organism burden and alveolar macrophage counts during infection with Pneumocystis carinii and recovery.  Clinical & Diagnostic Laboratory Immunology. 10(2):293-302, 2003 Mar.