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Eukaryotic Cell, February 2007, p. 280-290, Vol. 6, No. 2
1535-9778/07/$08.00+0     doi:10.1128/EC.00372-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mutations in Alternative Carbon Utilization Pathways in Candida albicans Attenuate Virulence and Confer Pleiotropic Phenotypes{triangledown}

Melissa A. Ramírez and Michael C. Lorenz*

Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston, Houston, Texas 77030

Received 22 November 2006/ Accepted 30 November 2006

The interaction between Candida albicans and cells of the innate immune system is a key determinant of disease progression. Transcriptional profiling has revealed that C. albicans has a complex response to phagocytosis, much of which is similar to carbon starvation. This suggests that nutrient limitation is a significant stress in vivo, and we have shown that glyoxylate cycle mutants are less virulent in mice. To examine whether other aspects of carbon metabolism are important in vivo during an infection, we have constructed strains lacking FOX2 and FBP1, which encode key components of fatty acid ß-oxidation and gluconeogenesis, respectively. As expected, fox2{Delta} mutants failed to utilize several fatty acids as carbon sources. Surprisingly, however, these mutants also failed to grow in the presence of several other carbon sources, whose assimilation is independent of ß-oxidation, including ethanol and citric acid. Mutants lacking the glyoxylate enzyme ICL1 also had more severe carbon utilization phenotypes than were expected. These results suggest that the regulation of alternative carbon metabolism in C. albicans is significantly different from that in other fungi. In vivo, fox2{Delta} mutants show a moderate but significant reduction in virulence in a mouse model of disseminated candidiasis, while disruption of the glyoxylate cycle or gluconeogenesis confers a severe attenuation in this model. These data indicate that C. albicans often encounters carbon-poor conditions during growth in the host and that the ability to efficiently utilize multiple nonfermentable carbon sources is a virulence determinant. Consistent with this in vivo requirement, C. albicans uniquely regulates carbon metabolism in a more integrated manner than in Saccharomyces cerevisiae, such that defects in one part of the machinery have wider impacts than expected. These aspects of alternative carbon metabolism may then be useful as targets for therapeutic intervention.

* Corresponding author. Mailing address: Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030. Phone: (713) 500-7422. Fax: (713) 500-5499. E-mail: Michael.Lorenz{at}uth.tmc.edu.

{triangledown} Published ahead of print on 8 December 2006.

Eukaryotic Cell, February 2007, p. 280-290, Vol. 6, No. 2
1535-9778/07/$08.00+0     doi:10.1128/EC.00372-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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