Limits...
The evolution of drug resistance in clinical isolates of Candida albicans.

Ford CB, Funt JM, Abbey D, Issi L, Guiducci C, Martinez DA, Delorey T, Li BY, White TC, Cuomo C, Rao RP, Berman J, Thompson DA, Regev A - Elife (2015)

Bottom Line: Studies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation.LOH events were commonly associated with acquired resistance, and SNPs in 240 genes may be related to host adaptation.Conversely, most aneuploidies were transient and did not correlate with drug resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Broad Institute of MIT and Harvard, Cambridge, United States.

ABSTRACT
Candida albicans is both a member of the healthy human microbiome and a major pathogen in immunocompromised individuals. Infections are typically treated with azole inhibitors of ergosterol biosynthesis often leading to drug resistance. Studies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation. Here, we leveraged next-generation sequencing to analyze 43 isolates from 11 oral candidiasis patients. We detected newly selected mutations, including single-nucleotide polymorphisms (SNPs), copy-number variations and loss-of-heterozygosity (LOH) events. LOH events were commonly associated with acquired resistance, and SNPs in 240 genes may be related to host adaptation. Conversely, most aneuploidies were transient and did not correlate with drug resistance. Our analysis also shows that isolates also varied in adherence, filamentation, and virulence. Our work reveals new molecular mechanisms underlying the evolution of drug resistance and host adaptation.

Show MeSH

Related in: MedlinePlus

Filamentation increases in many patient series.For several patient series, shown are the filamentation assay resultsafter 7 days of growth on Spider Media (‘Materials andMethods’). These data, a subset of which is shown in Figure 6, demonstrate theheterogeneity seen between strains, as well as the general trend forfilamentation to increase over time.DOI:http://dx.doi.org/10.7554/eLife.00662.018
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4383195&req=5

fig6s1: Filamentation increases in many patient series.For several patient series, shown are the filamentation assay resultsafter 7 days of growth on Spider Media (‘Materials andMethods’). These data, a subset of which is shown in Figure 6, demonstrate theheterogeneity seen between strains, as well as the general trend forfilamentation to increase over time.DOI:http://dx.doi.org/10.7554/eLife.00662.018

Mentions: To explore the possibility that some of the mutations reflect adaptation to otherfactors besides drug, we next measured phenotypes associated to virulence andinteraction with the host (‘Materials and methods’). Adhesion,filamentation, and virulence in a C. elegans model of infection(Jain et al., 2013) were measured for alarge panel of isolates (Figure 6, Figure 6—figure supplement 1, Figure 6—source data1). Additionally, we measured competitive fitness in standard tissueculture medium (RPMI) with and without drug in vitro (Figure 7).10.7554/eLife.00662.017Figure 6.Filamentation, adhesion and virulence increase concurrently withfitness.


The evolution of drug resistance in clinical isolates of Candida albicans.

Ford CB, Funt JM, Abbey D, Issi L, Guiducci C, Martinez DA, Delorey T, Li BY, White TC, Cuomo C, Rao RP, Berman J, Thompson DA, Regev A - Elife (2015)

Filamentation increases in many patient series.For several patient series, shown are the filamentation assay resultsafter 7 days of growth on Spider Media (‘Materials andMethods’). These data, a subset of which is shown in Figure 6, demonstrate theheterogeneity seen between strains, as well as the general trend forfilamentation to increase over time.DOI:http://dx.doi.org/10.7554/eLife.00662.018
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383195&req=5

fig6s1: Filamentation increases in many patient series.For several patient series, shown are the filamentation assay resultsafter 7 days of growth on Spider Media (‘Materials andMethods’). These data, a subset of which is shown in Figure 6, demonstrate theheterogeneity seen between strains, as well as the general trend forfilamentation to increase over time.DOI:http://dx.doi.org/10.7554/eLife.00662.018
Mentions: To explore the possibility that some of the mutations reflect adaptation to otherfactors besides drug, we next measured phenotypes associated to virulence andinteraction with the host (‘Materials and methods’). Adhesion,filamentation, and virulence in a C. elegans model of infection(Jain et al., 2013) were measured for alarge panel of isolates (Figure 6, Figure 6—figure supplement 1, Figure 6—source data1). Additionally, we measured competitive fitness in standard tissueculture medium (RPMI) with and without drug in vitro (Figure 7).10.7554/eLife.00662.017Figure 6.Filamentation, adhesion and virulence increase concurrently withfitness.

Bottom Line: Studies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation.LOH events were commonly associated with acquired resistance, and SNPs in 240 genes may be related to host adaptation.Conversely, most aneuploidies were transient and did not correlate with drug resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Broad Institute of MIT and Harvard, Cambridge, United States.

ABSTRACT
Candida albicans is both a member of the healthy human microbiome and a major pathogen in immunocompromised individuals. Infections are typically treated with azole inhibitors of ergosterol biosynthesis often leading to drug resistance. Studies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation. Here, we leveraged next-generation sequencing to analyze 43 isolates from 11 oral candidiasis patients. We detected newly selected mutations, including single-nucleotide polymorphisms (SNPs), copy-number variations and loss-of-heterozygosity (LOH) events. LOH events were commonly associated with acquired resistance, and SNPs in 240 genes may be related to host adaptation. Conversely, most aneuploidies were transient and did not correlate with drug resistance. Our analysis also shows that isolates also varied in adherence, filamentation, and virulence. Our work reveals new molecular mechanisms underlying the evolution of drug resistance and host adaptation.

Show MeSH
Related in: MedlinePlus