In host evolution of <i>Exophiala dermatitidis</i> in cystic fibrosis lung micro-environment

Kurbessoian, Tania; Murante, Daniel; Crocker, Alex W.; Hogan, Deborah A.; Stajich, Jason E.

doi:10.1101/2022.09.23.509114

“…We had previously identified a CF infection predominated by E. dermatiditis. We performed whole genome sequencing of twenty-three isolates and found a subpopulation of isolates with a non-synonymous SNP in the MRS4 (Figure 7A) (31). Subsequent Sanger sequencing confirmed that seven of the twenty three isolates carried an MRS4 ortholog with a sequence identical to the E. dermatiditis type strain, NIH8656 (referred to here as encoding Mrs4 40E-REF ).…”

Section: Mrs4 Mutations In Other Fungi Of Clinical Interestmentioning

confidence: 94%

Mrs4 loss of function in fungi during adaptation to the cystic fibrosis lung

Murante

¹

,

Demers

²

,

Kurbessoian

³

et al. 2023

Preprint

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The genetic disease cystic fibrosis (CF) frequently leads to chronic lung infections by bacteria and fungi. We identified three individuals with CF with persistent lung infections dominated by Clavispora (Candida) lusitaniae. Whole genome sequencing analysis of multiple isolates from each infection found evidence for selection for mutants in the gene MRS4 in all three distinct lung-associated populations. In each population, we found one or two unfixed, non-synonymous mutations in MRS4 relative to the reference allele found in multiple environmental and clinical isolates including the type strain. Genetic and phenotypic analyses found that all evolved alleles led to loss of function of Mrs4, a mitochondrial iron transporter. RNA Seq analyses found that Mrs4 variants with decreased activity led to increased expression of genes involved in iron acquisition mechanisms in both low iron and replete iron conditions. Furthermore, surface iron reductase activity and intracellular iron was much higher in strains with Mrs4 loss of function variants. Parallel studies found that a subpopulation of a CF-associated Exophiala dermatiditis infection also had a non-synonymous loss of function mutation in MRS4. Together, these data suggest that MRS4 mutations may be beneficial during chronic CF lung infections in diverse fungi perhaps for the purposes of adaptation to an iron restricted environment with chronic infections.

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“…The individual SRA read accession numbers and genome accession numbers for each isolate are listed in Table 1 . Genome assembly, annotation, and TEF1 phylogenetic assessment pipeline and related code are archived in Zenodo ( 40 ).…”

Section: Announcementmentioning

confidence: 99%

Genome Sequence and Assembly of 18 Fusarium Isolates from Florida Citrus under High Huanglongbing Disease Pressure and California Citrus under Low Huanglongbing Disease Pressure

Kurbessoian

¹

,

Heimlich-Villalta

²

,

Ginnan

³

et al. 2023

Microbiol Resour Announc

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The genomes of eighteen Fusarium isolates cultured from diseased and healthy citrus trees were sequenced, assembled, and annotated. Isolate species identification was confirmed using single marker (TEF1-alpha) phylogenetic assessment. Studies of the traits and genotypes of plant-associated isolates are important to understanding the fungal contribution to phytobiomes of citrus.

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Mrs4 loss of function in fungi during adaptation to the cystic fibrosis lung

Murante

¹

,

Demers

²

,

Kurbessoian

³

et al. 2023

mBio

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The genetic disease cystic fibrosis (CF) frequently leads to chronic lung infections by bacteria and fungi. We identified three individuals with CF with persistent lung infections dominated by Clavispora ( Candida ) lusitaniae . Whole-genome sequencing analysis of multiple isolates from each infection found evidence for selection for mutants in the gene MRS4 in all three distinct lung-associated populations. In each population, we found one or two unfixed, non-synonymous mutations in MRS4 relative to the reference allele found in multiple environmental and clinical isolates including the type strain. Genetic and phenotypic analyses found that all evolved alleles led to loss of function (LOF) of Mrs4, a mitochondrial iron transporter. RNA-seq analyses found that Mrs4 variants with decreased activity led to increased expression of genes involved in iron acquisition mechanisms in both low iron and replete iron conditions. Furthermore, surface iron reductase activity and intracellular iron were much higher in strains with Mrs4 LOF variants. Parallel studies found that a subpopulation of a CF-associated Exophiala dermatitidis infection also had a non-synonymous LOF mutation in MRS4 . Together, these data suggest that MRS4 mutations may be beneficial during chronic CF lung infections in diverse fungi, perhaps, for the purposes of adaptation to an iron-restricted environment with chronic infections. IMPORTANCE The identification of MRS4 mutations in Clavispora ( Candida ) lusitaniae and Exophiala dermatitidis in individuals with cystic fibrosis (CF) highlights a possible adaptive mechanism for fungi during chronic CF lung infections. The findings of this study suggest that loss of function of the mitochondrial iron transporter Mrs4 can lead to increased activity of iron acquisition mechanisms, which may be advantageous for fungi in iron-restricted environments during chronic infections. This study provides valuable information for researchers working toward a better understanding of the pathogenesis of chronic lung infections and more effective therapies to treat them.

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In host evolution of Exophiala dermatitidis in cystic fibrosis lung micro-environment

Cited by 3 publications

References 133 publications

Mrs4 loss of function in fungi during adaptation to the cystic fibrosis lung

Mrs4 loss of function in fungi during adaptation to the cystic fibrosis lung

Genome Sequence and Assembly of 18 Fusarium Isolates from Florida Citrus under High Huanglongbing Disease Pressure and California Citrus under Low Huanglongbing Disease Pressure

Mrs4 loss of function in fungi during adaptation to the cystic fibrosis lung

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