Journal
MOLECULAR MICROBIOLOGY
Volume 51, Issue 5, Pages 1447-1458Publisher
WILEY
DOI: 10.1111/j.1365-2958.2004.03921.x
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Funding
- NIAID NIH HHS [U01 AI48594, R01-AI50184, R01-AI051209, KO2-AI01577, AI47079, U01 AI47087] Funding Source: Medline
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Cryptococcus neoformans is a fungal pathogen most commonly causing meningitis in immunocompromised patients. Current therapies are inadequate, and novel antifungal targets are needed. We have identified by proteomics two thiol peroxidases that are differentially expressed at 37degreesC, the temperature of the mammalian host. Consistent with their antioxidant role, we show that the genes encoding these thiol-specific antioxidants, TSA1 and TSA3, are transcriptionally induced when C. neoformans is exposed to hydrogen peroxide. Genome sequence analysis of C. neoformans revealed a third thiol peroxidase, TSA4. We constructed single, double and triple mutants of the thiol peroxidase genes through homologous recombination and analysed their function by comparing the growth of these mutants with that of the wild-type strain. The tsa1Delta mutant shows sensitivity to hydrogen peroxide and t-butylhydroperoxide, as well as significant growth retardation at 25degreesC and 38.5degreesC. The tsa1Delta mutant is also sensitive to NO, demonstrating a link between oxidative and nitrosative stress pathways. In two mouse models of cryptococcosis, the tsa1Delta mutant is significantly less virulent.
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