Transcriptional Response ofCandida albicansto Nitric Oxide and the Role of theYHB1Gene in Nitrosative Stress and Virulence

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Abstract
Here, we investigate how Candida albicans, the most prevalent human fungal pathogen, protects itself from nitric oxide (.NO), an antimicrobial compound produced by the innate immune system. We show that exposure of C. albicans to.NO elicits a reproducible and specific transcriptional response as determined by genome-wide microarray analysis. Many genes are transiently induced or repressed by.NO, whereas a set of nine genes remain at elevated levels during.NO exposure. The most highly induced gene in this latter category is YHB1, a flavohemoglobin that detoxifies.NO in C. albicans and other microbes. We show that C. albicans strains deleted for YHB1 have two phenotypes in vitro; they are hypersensitive to.NO and they are hyperfilamentous. In a mouse model of disseminated candidiasis, a YHB1 deleted C. albicans strain shows moderately attenuated virulence, but the virulence defect is not suppressed by deletion of the host NOS2 gene. These results suggest that.NO production is not a prime determinant of virulence in the mouse tail vein model of candidiasis and that the attenuated virulence of a yhb1Δ/yhb1Δ strain is attributable to a defect other than its reduced ability to detoxify.NO.