The Candida glabrata sterol scavenging mechanism, mediated by the ATP‐binding cassette transporter Aus1p, is regulated by iron limitation

Abstract

SummaryDuring disseminated infection by the opportunistic pathogen Candida glabrata, uptake of sterols such as serum cholesterol may play a significant role during pathogenesis. The ATP-binding cassette transporter Aus1p is thought to function as a sterol importer and in this study, we show that uptake of exogenous sterols occurred under anaerobic conditions in wildtype cells of C. glabrata but not in AUS1-deleted mutant (aus1D) cells. In aerobic cultures, growth inhibition by fluconazole was prevented in the presence of serum, and AUS1 expression was upregulated. Uptake of sterol by azole treated cells required the presence of serum, and sterol alone did not reverse FLC inhibition of growth. However, if iron availability in the growth medium was limited by addition of the iron chelators ferrozine or apo-transferrin, growth of wild-type cells, but not aus1D cells, was rescued. In a mouse model of disseminated infection, the C. glabrata aus1D strain caused a significantly decreased kidney fungal burden than the wild-type strain or a strain in which AUS1 was restored. We conclude that sterol uptake in C. glabrata can occur in iron poor environment of host tissues and thus may contribute to C. glabrata pathogenesis.

Systematic Phenotyping of a Large-Scale Candida glabrata Deletion Collection Reveals Novel Antifungal Tolerance Genes

“…Azole resistance can be acquired through increased expression of genes encoding ABC transporters (Cdr1, Pdh1, Snq2) or changes in their transcriptional regulatory system (Pdr1, Gal11) [24]–[28]. Mitochondrial dysfunction [29] and serum utilization via the putative sterol transporter Aus1 [30], [31] also impact the ability of C. glabrata to tolerate high azole levels. Notably, calcineurin signaling has been implicated in azole tolerance in C. glabrata [32].…”

Medically Important Fungi Respond to Azole Drugs: An Update

“…Another C. glabrata specific resistance mechanism involves sterol import, and has been described recently [93][94][95][96]. Candida glabrata and the model organism S. cerevisiae are able to import extracellular sterols in quantities sufficient to replace endogenous ergosterol biosynthesis in the presence of azoles, although the exact conditions between these two organisms differ.…”

“…Both these organisms express the AUS1/PDR11 ABC type sterol importers [95,97], which have not been identified in other fungal species. Candida glabrata also imports high amounts of sterols when blocked in ergosterol biosynthesis by azoles, when grown in the presence of blood serum [94,96]. Candida glabrata also imports high amounts of sterols when blocked in ergosterol biosynthesis by azoles, when grown in the presence of blood serum [94,96].…”

The Ins and Outs of Azole Antifungal Drug Resistance: Molecular Mechanisms of Transport

“…To date, this phenomenon is related only to two fungal species -the model organism S. cerevisiae (Andreasen and Stier 1953) and the closely related pathogen C. glabrata (Zavrel et al 2013;Bard et al 2005;Nakayama et al 2007;Nagi et al 2013). Although C. albicans is also capable of sterol import, the rate is insufficient to replace the endogenous ergosterol biosynthesis (Zavrel et al 2013).…”

“…Additionally, sterol import is observed in mutants in early steps of ergosterol biosynthesis (ERG1, squalene epoxidase, or ERG7, lanosterol synthase) (Bard et al 2005). C. glabrata also imports small amounts of sterols aerobically, and this can be greatly stimulated in the presence of blood serum together with a block in ergosterol biosynthesis caused by azoles (Zavrel et al 2013;Nagi et al 2013). Thus, an azole-induced block in ergosterol biosynthesis can be compensated in vivo by sterol import from its host.…”