Journal article
AtrR Is an Essential Determinant of Azole Resistance in Aspergillus fumigatus
mBio, Vol.10(2), p.e02563-18
03/12/2019
DOI: 10.1128/mBio.02563-18
PMCID: PMC6414702
PMID: 30862750
Abstract
Aspergillosis associated with azole-resistant
has a mortality rate that can approach 90% in certain patient populations. The best-understood avenue for azole resistance involves changes in the
gene that encodes the target of azole drugs, lanosterol α-14 demethylase. The most common azole resistance allele currently described is a linked change corresponding to a change in the coding sequence of
and a duplication of a 34-bp region in the promoter leading to a tandem repeat (TR). Our previous studies identified a positively acting transcription factor called AtrR that binds to the promoter of
as well as that of an important membrane transporter protein gene called
In this work, we characterize two different mutant alleles of
, either an overproducing or an epitope-tagged form, causing constitutive activation of this factor. Using an epitope-tagged allele of
for chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq), the genomic binding sites for AtrR were determined. Close to 900 genes were found to have an AtrR response element (ATRE) in their promoter regions. Transcriptome evaluation by RNA sequencing (RNA-seq) indicated that both alleles led to elevated transcription of a subset of target genes. An electrophoretic mobility shift assay and DNase I protection mapping localized the ATREs in both the
and
promoters. The ATRE in
was located within the 34-bp repeat element. Virulence in a murine model was compromised when AtrR was either deleted or overproduced, indicating that the proper dosage of this factor is key for pathogenesis.
is the major filamentous fungal pathogen in humans. Infections associated with
are often treated with azole drugs, but resistance to these antifungal agents is increasing. Mortality from aspergillosis associated with azole-resistant fungi is extremely high. Previous work has identified transcriptional control of the azole drug target-encoding gene
as an important contributor to resistance in
Here, we demonstrate that the transcription factor AtrR binds to a region in the
promoter that is associated with alleles of this gene conferring clinically important azole resistance. Using high-throughput genomic technologies, we also uncover a large suite of target genes controlled by AtrR. These data indicate that AtrR coordinately regulates many different processes involved in drug resistance, metabolism, and virulence. Our new understanding of AtrR function provides important new insight into the pathogenesis of
.
Details
- Title: Subtitle
- AtrR Is an Essential Determinant of Azole Resistance in Aspergillus fumigatus
- Creators
- Sanjoy Paul - University of IowaMark Stamnes - University of IowaGrace Heredge Thomas - Roy J. and Lucille A. Carver College of MedicineHong Liu - The Lundquist InstituteDaisuke Hagiwara - University of TsukubaKatsuya Gomi - Tohoku UniversityScott G Filler - University of California, Los AngelesW Scott Moye-Rowley - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- mBio, Vol.10(2), p.e02563-18
- DOI
- 10.1128/mBio.02563-18
- PMID
- 30862750
- PMCID
- PMC6414702
- NLM abbreviation
- mBio
- ISSN
- 2161-2129
- eISSN
- 2150-7511
- Grant note
- R01 AI054928 / NIAID NIH HHS
- Language
- English
- Date published
- 03/12/2019
- Academic Unit
- Molecular Physiology and Biophysics; Internal Medicine
- Record Identifier
- 9984297607102771
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