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Eukaryotic Cell, January 2005, p. 46-54, Vol. 4, No. 1
1535-9778/05/$08.00+0     doi:10.1128/EC.4.1.46-54.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cryptococcus neoformans Mitochondrial Superoxide Dismutase: an Essential Link between Antioxidant Function and High-Temperature Growth

Steven S. Giles,1* Ines Batinic-Haberle,2 John R. Perfect,1,3 and Gary M. Cox1

Departments of Medicine,1 Molecular Genetics and Microbiology,3 Radiation Oncology, Duke University Medical Center, Durham, North Carolina2

Received 17 September 2004/ Accepted 13 October 2004

Manganese superoxide dismutase is an essential component of the mitochondrial antioxidant defense system of most eukaryotes. In the present study, we used a reverse-genetics approach to assess the contribution of the Cryptococcus neoformans manganese superoxide dismutase (Sod2) for antioxidant defense. Strains with mutations in the SOD2 gene exhibited increased susceptibility to oxidative stress as well as poor growth at elevated temperatures compared to isogenic wild-type strains. The sod2{Delta} mutants were also avirulent in a murine model of inhaled cryptococcosis. Reconstitution of a sod2{Delta} mutant restored Sod2 activity, eliminated the oxidative stress and temperature-sensitive (ts) phenotypes, and complemented the virulence phenotype. Characterization of the ts phenotype revealed a dependency between Sod2 antioxidant activity and the ability of C. neoformans cells to adapt to growth at elevated temperatures. The ts phenotype could be suppressed by the addition of either ascorbic acid (10 mM) or Mn salen (200 µM) at 30°C, but not at 37°C. Furthermore, sod2{Delta} mutant cells that were incubated for 24 h at 37°C under anaerobic, but not aerobic, conditions were viable when shifted to the permissive conditions of 25°C in the presence of air. These data suggest that the C. neoformans Sod2 is a major component of the antioxidant defense system in this human fungal pathogen and that adaptation to growth at elevated temperatures is also dependent on Sod2 activity.

* Corresponding author. Mailing address: Duke University Medical Center, Durham, NC 27710. Phone: (919) 668-3369. Fax: (919) 684-8902. E-mail: ssgiles{at}duke.edu.

Eukaryotic Cell, January 2005, p. 46-54, Vol. 4, No. 1
1535-9778/05/$08.00+0     doi:10.1128/EC.4.1.46-54.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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