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Infection and Immunity, July 2007, p. 3394-3405, Vol. 75, No. 7
0019-9567/07/$08.00+0     doi:10.1128/IAI.01977-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Eca1, a Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase, Is Involved in Stress Tolerance and Virulence in Cryptococcus neoformans{triangledown}

Weihua Fan ,1,{dagger},{ddagger} Alexander Idnurm,1,{dagger} Julia Breger,2 Eleftherios Mylonakis,2 and Joseph Heitman1*

Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710,1 Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts 021142

Received 17 December 2006/ Returned for modification 30 December 2006/ Accepted 1 May 2007

The basidiomycetous fungal pathogen Cryptococcus neoformans is adapted to survive challenges in the soil and environment and within the unique setting of the mammalian host. A C. neoformans mutant was isolated with enhanced virulence in a soil amoeba model that nevertheless exhibits dramatically reduced growth at mammalian body temperature (37°C). This mutant phenotype results from an insertion in the ECA1 gene, which encodes a sarcoplasmic/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA)-type calcium pump. Infection in murine macrophages, amoebae (Acanthamoeba castellanii), nematodes (Caenorhabditis elegans), and wax moth (Galleria mellonella) larvae revealed that the eca1 mutants are virulent or hypervirulent at permissive growth temperatures but attenuated at 37°C. Deletion mutants lacking the entire ECA1 gene were also hypersensitive to the calcineurin inhibitors cyclosporin and FK506 and to ER and osmotic stresses. An eca1{Delta} cna1{Delta} mutant lacking both Eca1 and the calcineurin catalytic subunit was more sensitive to high temperature and ER stresses than the single mutants and exhibited reduced survival in C. elegans and attenuated virulence towards wax moth larvae at temperatures that permit normal growth in vitro. Eca1 is likely involved in maintaining ER function, thus contributing to stress tolerance and virulence acting in parallel with Ca2+-calcineurin signaling.

* Corresponding author. Mailing address: Room 322 CARL Building, Box 3546, Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-2824. Fax: (919) 684-5458. E-mail: heitm001{at}duke.edu

{triangledown} Published ahead of print on 14 May 2007.

Editor: A. Casadevall

{dagger} W.F. and A.I. contributed equally to this study.

{ddagger} Present address: BASF Plant Science, 26 Davis Drive, Research Triangle Park, NC 27709.

Infection and Immunity, July 2007, p. 3394-3405, Vol. 75, No. 7
0019-9567/07/$08.00+0     doi:10.1128/IAI.01977-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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  • Idnurm, A., Walton, F. J., Floyd, A., Reedy, J. L., Heitman, J. (2009). Identification of ENA1 as a Virulence Gene of the Human Pathogenic Fungus Cryptococcus neoformans through Signature-Tagged Insertional Mutagenesis. Eukaryot Cell 8: 315-326 [Abstract] [Full Text]  


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