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Infection and Immunity, January 2003, p. 173-180, Vol. 71, No. 1
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.1.173-180.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Superoxide Dismutase Influences the Virulence of Cryptococcus neoformans by Affecting Growth within Macrophages

Gary M. Cox,1* Thomas S. Harrison,2 Henry C. McDade,1 Carlos P. Taborda,3 Garrett Heinrich,1 Arturo Casadevall,3 and John R. Perfect1

Departments of Medicine and Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina,1 Department of Infectious Diseases, St. George's Hospital Medical School, London, United Kingdom,2 Departments of Medicine and Microbiology and Immunology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York3

Received 31 July 2002/ Returned for modification 30 August 2002/ Accepted 5 October 2002

Superoxide dismutase (SOD) is an enzyme that converts superoxide radicals into hydrogen peroxide and molecular oxygen and has been shown to contribute to the virulence of many human-pathogenic bacteria through its ability to neutralize toxic levels of reactive oxygen species generated by the host. SOD has also been speculated to be important in the pathogenesis of fungal infections, but the role of this enzyme has not been rigorously investigated. To examine the contribution of SOD to the pathogenesis of fungal infections, we cloned the Cu,Zn SOD-encoding gene (SOD1) from the human-pathogenic yeast Cryptococcus neoformans and made mutants via targeted disruption. The sod1 mutant strains had marked decreases in SOD activity and were strikingly more susceptible to reactive oxygen species in vitro. A sod1 mutant was significantly less virulent than the wild-type strain and two independent reconstituted strains, as measured by cumulative survival in the mouse inhalational model. In vitro studies established that the sod1 strain had attenuated growth compared to the growth of the wild type and a reconstituted strain inside macrophages producing reduced amounts of nitric oxide. These findings demonstrate that (i) the Cu,Zn SOD contributes to virulence but is not required for pathogenicity in C. neoformans; (ii) the decreased virulence of the sod1 strain may be due to increased susceptibility to oxygen radicals within macrophages; and (iii) other antioxidant defense systems in C. neoformans can compensate for the loss of the Cu,Zn SOD in vivo.

* Corresponding author. Mailing address: Box 3281, Duke Medical Center, Durham, NC 27710. Phone: (919) 681-5055. Fax: (919) 684-8902. E-mail: gary.cox{at}duke.edu.

Editor: T. R. Kozel

Infection and Immunity, January 2003, p. 173-180, Vol. 71, No. 1
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.1.173-180.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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