Candida albicans uses multiple mechanisms to acquire the essential metabolite inositol during infection.
Candida albicans is an important cause of life-threatening systemic bloodstream infections in immunocompromised patients. In order to cause infections, C. albicans must be able to synthesize the essential metabolite inositol or acquire it from the host. Based on the similarity of C. albicans to Saccharomyces cerevisiae, it was predicted that C. albicans may generate inositol de novo, import it from the environment, or both. The C. albicans inositol synthesis gene INO1 (orf19.7585) and inositol transporter gene ITR1 (orf19.3526) were each disrupted. The ino1Delta/ino1Delta mutant was an inositol auxotroph, and the itr1Delta/itr1Delta mutant was unable to import inositol from the medium. Each of these mutants was fully virulent in a mouse model of systemic infection. It was not possible to generate an ino1Delta/ino1Delta itr1Delta/itr1Delta double mutant, suggesting that in the absence of these two genes, C. albicans could not acquire inositol and was nonviable. A conditional double mutant was created by replacing the remaining wild-type allele of ITR1 in an ino1Delta/ino1Delta itr1Delta/ITR1 strain with a conditionally expressed allele of ITR1 driven by the repressible MET3 promoter. The resulting ino1Delta/ino1Delta itr1Delta/P(MET3)::ITR1 strain was found to be nonviable in medium containing methionine and cysteine (which represses the P(MET3) promoter), and it was avirulent in the mouse model of systemic candidiasis. These results suggest a model in which C. albicans has two equally effective mechanisms for obtaining inositol while in the host. It can either generate inositol de novo through Ino1p, or it can import it from the host through Itr1p.
Chen
Ying-Lien
YL
Department of Microbiology, University of Tennessee, Knoxville, TN 37996, USA.
Kauffman
Sarah
S
Reynolds
Todd B
TB
D000818:Animals; D002176:Candida albicans / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D002177:Candidiasis / Q000382:microbiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000502:physiology; D007294:Inositol / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation; D014774:Virulence
D002352:Carrier Proteins; D005656:Fungal Proteins; D007294:Inositol