Loss of Upc2p-Inducible Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity.

Inactivation of sterol Δ-desaturase (Erg3p) in the prevalent fungal pathogen is one of several mechanisms that can confer resistance to the azole antifungal drugs. However, loss of Erg3p activity is also associated with deficiencies in stress tolerance, invasive hyphal growth, and attenuated virulence in a mouse model of disseminated infection. This may explain why relatively few -deficient strains have been reported among azole-resistant clinical isolates. In this study, we examined the consequences of Erg3p inactivation upon pathogenicity and azole susceptibility in mouse models of mucosal and disseminated infection. While a Δ/Δ mutant was unable to cause lethality in the disseminated model, it induced pathology in a mouse model of vaginal infection. The Δ/Δ mutant was also more resistant to fluconazole treatment than the wild type in both models of infection. Thus, complete loss of Erg3p activity confers azole resistance but also niche-specific virulence deficiencies. Serendipitously, we discovered that loss of azole-inducible transcription (rather than complete inactivation) is sufficient to confer fluconazole resistance, without compromising stress tolerance, hyphal growth, or pathogenicity in either mouse model. It is also sufficient to confer fluconazole resistance in the mouse vaginal model, but not in the disseminated model of infection, and thus confers niche-specific azole resistance without compromising pathogenicity at either site. Collectively, these results establish that modulating Erg3p expression or activity can have niche-specific consequences on both pathogenicity and azole resistance. While conferring resistance to the azole antifungals , loss of sterol Δ-desaturase (Erg3p) activity has also been shown to reduce pathogenicity. Accordingly, it has been presumed that this mechanism may not be significant in the clinical setting. The results presented here challenge this assumption, revealing a more complex relationship between Erg3p activity, azole resistance, pathogenicity, and the specific site of infection. Most importantly, we have shown that even modest changes in transcription are sufficient to confer azole resistance without compromising fitness or pathogenicity. Given that previous efforts to assess the importance of as a determinant of clinical azole resistance have focused almost exclusively on detecting null mutants, its role may have been grossly underestimated. On the basis of our results, a more thorough investigation of the contribution of the gene to azole resistance in the clinical setting is warranted.