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Infection and Immunity, August 2009, p. 3344-3354, Vol. 77, No. 8
0019-9567/09/$08.00+0     doi:10.1128/IAI.00299-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Effects of Decreased Calmodulin Protein on the Survival Mechanisms of Alveolar Macrophages during Pneumocystis Pneumonia{triangledown}

Mark E. Lasbury,* Pamela J. Durant, Chung-Ping Liao, and Chao-Hung Lee

Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202

Received 16 March 2009/ Returned for modification 9 May 2009/ Accepted 23 May 2009

Pneumocystis infection causes increased intracellular levels of reactive oxygen species (ROS) and the subsequent apoptosis of alveolar macrophages (Amø). Assessments of key prosurvival molecules in Amø and bronchoalveolar lavage fluids from infected rats and mice showed low levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and reduced activation of phosphoinositide-3 kinase (PI-3K). Ubiquitous calcium-sensing protein calmodulin protein and mRNA levels were also reduced in Amø during Pneumocystis pneumonia (Pcp). Calmodulin has been implicated in control of GM-CSF production and PI-3K activation in other immune cell types. Experiments to determine the control of GM-CSF and PI-3K by calmodulin in Amø showed that GM-CSF expression and PI-3K activation could not be induced when calmodulin was inhibited. Calmodulin inhibition also led to increased levels of ROS and apoptosis in cells exposed to bronchoalveolar lavage fluids from infected animals. Supplementation of Amø with exogenous calmodulin increased survival signaling via GM-CSF and PI-3K and reduced ROS and apoptosis. These data support the hypotheses that calmodulin levels at least partially control survival signaling in Amø and that restoration of GM-CSF or PI-3K signaling will improve host response to the organism.

* Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Fesler Hall, Room 406, 1120 South Dr., Indianapolis, IN 46202-5112. Phone: (317) 274-4606. Fax: (317) 278-0643. E-mail: melasbur{at}iupui.edu

{triangledown} Published ahead of print on 1 June 2009.

Editor: A. Casadevall

Infection and Immunity, August 2009, p. 3344-3354, Vol. 77, No. 8
0019-9567/09/$08.00+0     doi:10.1128/IAI.00299-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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