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Infection and Immunity, November 2003, p. 6463-6471, Vol. 71, No. 11
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.11.6463-6471.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Lung Epithelial Cells and Extracellular Matrix Components Induce Expression of Pneumocystis carinii STE20, a Gene Complementing the Mating and Pseudohyphal Growth Defects of ste20 Mutant Yeast

Theodore J. Kottom,1 Julia R. Köhler,2,3 Charles F. Thomas Jr.,1 Gerald R. Fink,3 and Andrew H. Limper1*

Thoracic Diseases Research Unit, Departments of Internal Medicine and Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, MinnesotaDivision of Infectious Disease, Children’s Hospital,1 Department of Cell Biology, Whitehead Institute for Biomedical Research,2 Cambridge, Massachusetts3

Received 20 February 2003/ Returned for modification 21 April 2003/ Accepted 11 August 2003

Pneumocystis carinii causes severe pneumonia in immunocompromised hosts. The binding of P. carinii to alveolar epithelial cells and extracellular matrix constituents such as fibronectin and vitronectin is a central feature of infection, which initiates proliferation of the organism. Herein, we demonstrate that P. carinii binding to lung cells specifically alters the gene expression of the organism, regulating fungal growth. Subtractive hybridization was performed to isolate P. carinii genes expressed following binding to mammalian extracellular matrix constituents. P. carinii STE20 (PCSTE20), a gene participating in mating and pseudohyphal growth of other fungi, was identified following adherence to the extracellular matrix constituents fibronectin, vitronectin, collagen, and lung epithelial cells. The expression of PCSTE20 and a related P. carinii mitogen-activated protein kinase (MAPK) kinase gene, also implicated in signaling of mating, were both specifically upregulated by binding to matrix protein. The expression of general cyclin-dependent kinases and other MAPKs not involved in mating pathways were not altered by organism binding. PCSTE20 expression was also strongly enhanced following organism attachment to A549 lung epithelial cells. When expressed in a Saccharomyces cerevisiae ste20{Delta} mutant, PCSTE20 suppressed defects in both mating and pseudohyphal growth. These findings are consistent with the observed proliferation and filopodial extension of Pneumocystis organisms adherent to the epithelium in the lungs of immunocompromised hosts. PCSTE20 expression appears to represent a significant component in the regulation of the life cycle of this intractable opportunistic pathogen.

* Corresponding author. Mailing address: 8-24 Stabile Building, Mayo Clinic, Rochester, MN 55905. Phone: (507) 284-2964. Fax: (507) 284-4521. E-mail: limper.andrew{at}mayo.edu.

Editor: T. R. Kozel

Infection and Immunity, November 2003, p. 6463-6471, Vol. 71, No. 11
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.11.6463-6471.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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