A Population Genomics Approach to Assessing the Genetic Basis of Within-Host Microevolution Underlying Recurrent Cryptococcal Meningitis Infection

Rhodes, Johanna; Beale, Mathew A.; Vanhove, Mathieu; Jarvis, Joseph N; Kannambath, Shichina; Simpson, John; Ryan, Anthea; Meintjes, Graeme; Harrison, Thomas S.; Fisher, Matthew C.; Bicanic, Tihana

doi:10.1534/g3.116.037499

Cited by 86 publications

(111 citation statements)

References 65 publications

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“…Evolutionary theory predicts that hypermutators should be rare in eukaryotic microbes because sex unlinks mutator alleles from the mutations they generate, eliminating the advantage of an elevated mutation rate and leaving only the general decrease in fitness from introduced mutations 34 . This result lends further support to the recent appreciation that mismatch repair mutants may be common in pathogenic fungi in part because treatment with antifungal drugs increases selection for mutations that generate resistance 13,14,16,17 .…”

Section: Discussionsupporting

confidence: 72%

“…Recent work has demonstrated one source of increased rates of resistance to antifungal drugs in Cryptococcus: defects in the DNA mismatch repair pathway 13,14 . Natural isolates with DNA mismatch repair defects have been identified in both an outbreak population of Cryptococcus deuterogattii 13,15 and in Cryptococcus neoformans 14,16 . Defects in mismatch repair are also common in other human fungal pathogens, including Candida glabrata 17 .…”

mentioning

confidence: 99%

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5-fluorocytosine resistance is associated with hypermutation and alterations in capsule biosynthesis in Cryptococcus

Billmyre

Clancey

et al. 2020

Nat Commun

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Patients infected with the fungal pathogen Cryptococcus are most effectively treated with a combination of 5-fluorocytosine (5FC) and amphotericin B. 5FC acts as a prodrug, which is converted into toxic 5-fluorouracil (5FU) upon uptake into fungal cells. However, the pathogen frequently develops resistance through unclear mechanisms. Here we show that resistance to 5FC in Cryptococcus deuterogattii is acquired more frequently in isolates with defects in DNA mismatch repair that confer an elevated mutation rate. We use whole genome sequencing of 16 independent isolates to identify mutations associated with 5FC resistance in vitro. We find mutations in known resistance genes (FUR1 and FCY2) and in a gene UXS1, previously shown to encode an enzyme that converts UDP-glucuronic acid to UDP-xylose for capsule biosynthesis, but not known to play a role in 5FC metabolism. Mutations in UXS1 lead to accumulation of UDP-glucuronic acid and alterations in nucleotide metabolism, which appear to suppress toxicity of both 5FC and its toxic derivative 5FU.

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Section: Discussionsupporting

confidence: 72%

mentioning

confidence: 99%

5-fluorocytosine resistance is associated with hypermutation and alterations in capsule biosynthesis in Cryptococcus

Billmyre

Clancey

et al. 2020

Nat Commun

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“…Patients treated for cryptococcal meningitis often relapse due to gain of resistance to antifungal drugs (35). Mutations in MSH2 provide the pathogen with an opportunity for the rapid evolution of resistance to antifungal drugs and could be a cause of patient relapse.…”

Section: Discussionmentioning

confidence: 99%

Mismatch Repair of DNA Replication Errors Contributes to Microevolution in the Pathogenic Fungus Cryptococcus neoformans

Boyce

Wang

Verma

et al. 2017

mBio

111

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The ability to adapt to a changing environment provides a selective advantage to microorganisms. In the case of many pathogens, a large change in their environment occurs when they move from a natural setting to a setting within a human host and then during the course of disease development to various locations within that host. Two clinical isolates of the human fungal pathogen Cryptococcus neoformans were identified from a collection of environmental and clinical strains that exhibited a mutator phenotype, which is a phenotype which provides the ability to change rapidly due to the accumulation of DNA mutations at high frequency. Whole-genome analysis of these strains revealed mutations in MSH2 of the mismatch repair pathway, and complementation confirmed that these mutations are responsible for the mutator phenotype. Comparison of mutation frequencies in deletion strains of eight mismatch repair pathway genes in C. neoformans showed that the loss of three of them, MSH2, MLH1, and PMS1, results in an increase in mutation rates. Increased mutation rates enable rapid microevolution to occur in these strains, generating phenotypic variations in traits associated with the ability to grow in vivo, in addition to allowing rapid generation of resistance to antifungal agents. Mutation of PMS1 reduced virulence, whereas mutation of MSH2 or MLH1 had no effect on the level of virulence. These findings thus support the hypothesis that this pathogenic fungus can take advantage of a mutator phenotype in order to cause disease but that it can do so only in specific pathways that lead to a mutator trait without a significant tradeoff in fitness.

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“…Struc-tural genomic plasticity can result in resistance, with chromosome arm duplications leading to efflux pump and target-site overexpression in C. albicans (24,26). Hypermutator strains of C. glabrata and Cryptococcus neoformans, with the potential to evolve rapidly in response to host and drug selection, were recently reported (27,28).…”

Section: Parallel Evolution Of Resistance Mechanisms In the Clinic Anmentioning

confidence: 99%

Worldwide emergence of resistance to antifungal drugs challenges human health and food security

Fisher

Hawkins

Sanglard

et al. 2018

Science

1,049

917

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The recent rate of emergence of pathogenic fungi that are resistant to the limited number of commonly used antifungal agents is unprecedented. The azoles, for example, are used not only for human and animal health care and crop protection but also in antifouling coatings and timber preservation. The ubiquity and multiple uses of azoles have hastened the independent evolution of resistance in many environments. One consequence is an increasing risk in human health care from naturally occurring opportunistic fungal pathogens that have acquired resistance to this broad class of chemicals. To avoid a global collapse in our ability to control fungal infections and to avoid critical failures in medicine and food security, we must improve our stewardship of extant chemicals, promote new antifungal discovery, and leverage emerging technologies for alternative solutions.

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A Population Genomics Approach to Assessing the Genetic Basis of Within-Host Microevolution Underlying Recurrent Cryptococcal Meningitis Infection

Cited by 86 publications

References 65 publications

5-fluorocytosine resistance is associated with hypermutation and alterations in capsule biosynthesis in Cryptococcus

5-fluorocytosine resistance is associated with hypermutation and alterations in capsule biosynthesis in Cryptococcus

Mismatch Repair of DNA Replication Errors Contributes to Microevolution in the Pathogenic Fungus Cryptococcus neoformans

Worldwide emergence of resistance to antifungal drugs challenges human health and food security

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