title: The Candida glabrata sterol scavenging mechanism, mediated by the ATP-binding cassette transporter Aus1p, is regulated by iron limitation.
abstract: During 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 wild-type cells of C. glabrata but not in AUS1-deleted mutant (aus1Δ) 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 aus1Δ cells, was rescued. In a mouse model of disseminated infection, the C. glabrata aus1Δ 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.
authors: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
authors: Minoru
authors: M
authors: Nagi
authors: Koichi
authors: K
authors: Tanabe
authors: Keigo
authors: K
authors: Ueno
authors: Hironobu
authors: H
authors: Nakayama
authors: Toshihiro
authors: T
authors: Aoyama
authors: Hiroji
authors: H
authors: Chibana
authors: Satoshi
authors: S
authors: Yamagoe
authors: Takashi
authors: T
authors: Umeyama
authors: Takahiro
authors: T
authors: Oura
authors: Hideaki
authors: H
authors: Ohno
authors: Susumu
authors: S
authors: Kajiwara
authors: Yoshitsugu
authors: Y
authors: Miyazaki
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000332:Aerobiosis; D000693:Anaerobiosis; D000818:Animals; D041221:Candida glabrata / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D002177:Candidiasis / Q000382:microbiology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D007501:Iron / Q000378:metabolism*; D007668:Kidney / Q000382:microbiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000382:microbiology; D013261:Sterols / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D005656:Fungal Proteins; D013261:Sterols; D007501:Iron