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In the present study, we used a reverse-genetics approach to assess the contribution of the<jats:italic>Cryptococcus neoformans<\/jats:italic>manganese superoxide dismutase (Sod2) for antioxidant defense. Strains with mutations in the<jats:italic>SOD2<\/jats:italic>gene exhibited increased susceptibility to oxidative stress as well as poor growth at elevated temperatures compared to isogenic wild-type strains. The<jats:italic>sod2<\/jats:italic>\u0394 mutants were also avirulent in a murine model of inhaled cryptococcosis. Reconstitution of a<jats:italic>sod2<\/jats:italic>\u0394 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<jats:italic>C. neoformans<\/jats:italic>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 \u03bcM) at 30\u00b0C, but not at 37\u00b0C. Furthermore,<jats:italic>sod2<\/jats:italic>\u0394 mutant cells that were incubated for 24 h at 37\u00b0C under anaerobic, but not aerobic, conditions were viable when shifted to the permissive conditions of 25\u00b0C in the presence of air. These data suggest that the<jats:italic>C. neoformans<\/jats:italic>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.<\/jats:p>","DOI":"10.1128\/ec.4.1.46-54.2005","type":"journal-article","created":{"date-parts":[[2005,1,11]],"date-time":"2005-01-11T01:16:15Z","timestamp":1105406175000},"page":"46-54","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":101,"title":["<i>Cryptococcus neoformans<\/i>Mitochondrial Superoxide Dismutase: an Essential Link between Antioxidant Function and High-Temperature Growth"],"prefix":"10.1128","volume":"4","author":[{"given":"Steven S.","family":"Giles","sequence":"first","affiliation":[{"name":"Departments of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Batinic\u0301-Haberle","sequence":"additional","affiliation":[{"name":"Radiation Oncology, Duke University Medical Center, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Perfect","sequence":"additional","affiliation":[{"name":"Departments of Medicine"},{"name":"Molecular Genetics and Microbiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary M.","family":"Cox","sequence":"additional","affiliation":[{"name":"Departments of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.10.5794-5802.2003"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(02)49337-8"},{"key":"e_1_3_2_4_2","first-page":"2689","volume":"2002","year":"2002","unstructured":"Batinic-Haberle, I., I. 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