Abstract
ABSTRACTInactivation of sterol Δ5,6-desaturase (Erg3p) in the prevalent fungal pathogen Candida albicans 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 erg3-deficient strains have been reported among azole-resistant clinical isolates. In this study, we examined the consequences of Erg3p inactivation upon C. albicans pathogenicity and azole susceptibility in mouse models of mucosal and disseminated infection. While a C. albicans erg3Δ/Δ mutant was unable to cause lethality in the disseminated model, it induced pathology in a mouse model of vaginal infection. The erg3Δ/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 ERG3 transcription (rather than complete inactivation) is sufficient to confer in vitro fluconazole resistance, without compromising C. albicans 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 C. albicans pathogenicity at either site. Collectively, these results establish that modulating Erg3p expression or activity can have niche-specific consequences on both C. albicans pathogenicity and azole resistance.
Highlights
Inactivation of sterol Δ5,6-desaturase (Erg3p) in the prevalent fungal pathogen Candida albicans is one of several mechanisms that can confer resistance to the azole antifungal drugs
The significance of ERG3 inactivating mutations to azole resistance in the clinical setting has been further brought into question by the finding that a C. albicans erg3⌬/⌬ mutant is susceptible to azole treatment in a mouse model of disseminated infection, despite in vitro resistance [23]
Altering ERG3 transcription is sufficient to induce in vitro azole resistance without compromising Candida albicans fitness
Summary
Inactivation of sterol Δ5,6-desaturase (Erg3p) in the prevalent fungal pathogen Candida albicans is one of several mechanisms that can confer resistance to the azole antifungal drugs. We discovered that loss of azole-inducible ERG3 transcription (rather than complete inactivation) is sufficient to confer in vitro fluconazole resistance, without compromising C. albicans stress tolerance, hyphal growth, or pathogenicity in either mouse model. The significance of ERG3 inactivating mutations to azole resistance in the clinical setting has been further brought into question by the finding that a C. albicans erg3⌬/⌬ mutant is susceptible to azole treatment in a mouse model of disseminated infection, despite in vitro resistance [23]. To date, the consequences of Erg3p inactivation upon C. albicans pathogenicity and azole resistance at mucosal body sites has not been directly tested This is important, as we previously reported that C. albicans erg2⌬/⌬ and erg24⌬/⌬ ergosterol biosynthetic mutants (lacking C-8 sterol isomerase and C-14 sterol reductase, respectively), are essentially avirulent in the disseminated model but readily colonize the mouse vagina [26]. In the course of conducting these studies, we serendipitously discovered that altering the regulation of ERG3 transcription is sufficient to induce in vitro and niche-specific in vivo azole resistance, without compromising the pathogenic fitness of the fungus
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