# Evolved Heterogeneity Contributes to Chronic Fungal Lung Infections

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2020 · $403,221

## Abstract

Chronic fungal infections are often recalcitrant to treatment. The recalcitrance of chronic infections is not well
understood, but likely involves multiple factors including biofilm formation, and slow growth. In addition, diverse
studies in different systems from bacterial infections to human tumors, found that populations can have
heterogeneous drug susceptibilities even before treatment is initiated, leading to treatment failures.
Heterogeneity within populations of fungal pathogens has not been well studied. We have identified chronic
high burden C. lusitaniae lung infections in three unrelated subjects with cystic fibrosis (CF). C. lusitaniae has
been documented in CF lung infections previously, but infections dominated by C. lusitaniae are not widely
reported. In all three subjects, C. lusitaniae isolates within each population showed high variance in antifungal
sensitivity, measured as the minimum inhibitory concentration (MIC), with some isolates stably resistant. We
characterized the isolates from one subject further and discovered, through whole genome sequencing, that
variable MICs correlated with heterogeneity in alleles of MRR1, a gene associated with clinical drug resistance
in other Candida spp. exposed to drugs. Variation in MRR1 alleles within a single population was surprising as
this subject had not been prescribed antifungals in the preceding year. Because of the ease of manipulation of
C. lusitaniae, a haploid, genetically tractable, mating competent, yeast, we propose to leverage these isolate
collections to study the basis for drug resistance, factors that promote selection for increased drug resistance,
and factors that promote heterogeneous population structures in the lung. In Aim 1, we will test the hypothesis
that substitutions in the Mrr1 central regulatory domain and Mrr1 C-terminal truncations lead to increased
activity (1.1), that common and distinct genes are controlled by different classes of Mrr1 variants (1.2), and that
differentially expressed Mrr1-regulated genes contribute to fluconazole resistance (1.3). In Aim 2, we will test
the hypothesis that specific SNPs impact metabolic diversity (2.1), high Mrr1 activity promotes fitness in
isolates with high rates of glycolysis (2.2), and that metabolic diversification promotes heterogeneity in drug
resistance in nutritionally complex environments (2.3). Because of the propensity of C. lusitaniae to develop
resistance to potent drugs like amphotericin B, often the antifungal of last resort, and the close relationship
between C. lusitaniae and a recent multi-drug resistant fungal pathogen of concern, Candida auris, these
studies are highly relevant to discovering ways to better understand the composition of chronic infections, to
limit the development of antifungal resistance, and to combat resistant isolates once they develop.

## Key facts

- **NIH application ID:** 9967997
- **Project number:** 5R01AI127548-04
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** DEBORAH A HOGAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,221
- **Award type:** 5
- **Project period:** 2017-07-19 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967997

## Citation

> US National Institutes of Health, RePORTER application 9967997, Evolved Heterogeneity Contributes to Chronic Fungal Lung Infections (5R01AI127548-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9967997. Licensed CC0.

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