# Identification of virulence determinants under the transcriptional control of AtrR in Aspergillus fumigatus

> **NIH NIH R21** · UNIVERSITY OF IOWA · 2020 · $250,670

## Abstract

Aspergillus fumigatus is the major human filamentous fungal pathogen. Azole drugs represent
the gold standard in treatment of aspergillosis and are the only agent that can be used without
hospitalization. Problematic findings in Western Europe have shown that azole resistant forms
of A. fumigatus can arise and spread frequently. These studies have demonstrated that the
primary cause of azole resistance is a compound mutation in the gene encoding the target
enzyme for azole drugs, cyp51A. These linked mutations consist of an alteration in the
promoter sequence (tandem duplication of 34 base pairs: TR34) coupled with an amino acid
replacement in the coding sequence (L98H) in cyp51A. Mutant strains containing this TR34
L98H cyp51A allele are highly azole drug resistant and appear to have no fitness defect, leading
to the high frequency of resistant infections. We have discovered a new transcription factor
called AtrR that binds to this TR34 element and is required for normal cyp51A expression.
Importantly, both we and others have found that atrR null mutants are avirulent in a mouse
inhalation model of infection. Here we propose to use a chromatin immunoprecipitation coupled
with high-throughput sequencing (ChIP-seq) dataset that we have generated to identify genes
under control of AtrR that impact virulence. We will use a mouse infection model to determine
AtrR-regulated genes that exhibit transcriptional responses in the infected mouse lung.
Nanostring technology will be employed to allow measurement of fungal gene expression in the
high background of mammalian RNA. AtrR target genes will be rank ordered by their in vivo
expression profile. We will use CRISPR technology and existing disruption collections to
assess the role of up to 40 AtrR target genes for their effect on an in vitro epithelial cell damage
assay. Our goal will be to prioritize these genes based on their in vivo expression profile and
impact on epithelial cell damage. From these analyses, we will select up to 8 target gene
disruption mutants to screen for an effect on virulence using our mouse inhalation model. This
work will provide the first examination of the molecular basis of AtrR-mediated virulence factors
that are critical for pathogenesis in this animal model of infected lungs.

## Key facts

- **NIH application ID:** 9914775
- **Project number:** 1R21AI145316-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** W Scott Moye-Rowley
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $250,670
- **Award type:** 1
- **Project period:** 2020-01-24 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914775

## Citation

> US National Institutes of Health, RePORTER application 9914775, Identification of virulence determinants under the transcriptional control of AtrR in Aspergillus fumigatus (1R21AI145316-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9914775. Licensed CC0.

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