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Eukaryotic Cell, August 2005, p. 1420-1433, Vol. 4, No. 8
1535-9778/05/$08.00+0     doi:10.1128/EC.4.8.1420-1433.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cryptococcus neoformans Gene Expression during Murine Macrophage Infection{dagger}

Weihua Fan,1 Peter R. Kraus,1,{ddagger} Marie-Josee Boily,1,§ and Joseph Heitman1,2,3,4*

Departments of Molecular Genetics and Microbiology,1 Medicine,2 Pharmacology and Cancer Biology,3 Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 277104

Received 5 May 2005/ Accepted 3 June 2005

The fungal pathogen Cryptococcus neoformans survives phagocytosis by macrophages and proliferates within, ultimately establishing latent infection as a facultative intracellular pathogen that can escape macrophage control to cause disseminated disease. This process is hypothesized to be important for C. neoformans pathogenesis; however, it is poorly understood how C. neoformans adapts to and overcomes the hostile intracellular environment of the macrophage. Using DNA microarray technology, we have investigated the transcriptional response of C. neoformans to phagocytosis by murine macrophages. The expression profiles of several genes were verified using quantitative reverse transcription-PCR and a green fluorescent protein reporter strain. Multiple membrane transporters for hexoses, amino acids, and iron were up-regulated, as well as genes involved in responses to oxidative stress. Genes involved in autophagy, peroxisome function, and lipid metabolism were also induced. Interestingly, almost the entire mating type locus displayed increased expression 24 h after internalization, suggesting an intrinsic connection between infection and the MAT locus. Genes in the Gpa1-cyclic AMP-protein kinase A pathway were also up-regulated. Both gpa1 and pka1 mutants were found to be compromised in macrophage infection, confirming the important role of this virulence pathway. A large proportion of the repressed genes are involved in ribosome-related functions, rRNA processing, and translation initiation/elongation, implicating a reduction in translation as a central response to phagocytosis. In summary, this gene expression profile allows us to interpret the adaptation of C. neoformans to the intracellular infection process and informs the search for genes encoding novel virulence attributes.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, 322 CARL Building, Research Dr., Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-2824. Fax: (919) 684-5458. E-mail: heitm001{at}duke.edu.

{dagger} Supplemental material for this article may be found at http://ec.asm.org/.

{ddagger} Present address: Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06620.

§ Present address: Département Chimie-biologie, Université du Québec à Trois-Rivières, 3351 Boul. des Forges, Trois-Rivières, Québec G9A 5H7, Canada.

Eukaryotic Cell, August 2005, p. 1420-1433, Vol. 4, No. 8
1535-9778/05/$08.00+0     doi:10.1128/EC.4.8.1420-1433.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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