It's not all about us: evolution and maintenance of<i>Cryptococcus</i>virulence requires selection outside the human host

Gerstein, Aleeza C.; Nielsen, Kirsten

doi:10.1002/yea.3222

Cited by 18 publications

(13 citation statements)

References 104 publications

(116 reference statements)

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“…The comparison between other human pathogenic fungi and their wild relatives on trees is proving to be important for an understanding of their pathogenicity (Gerstein and Nielsen, 2017). Futhermore, study of the natural enemies of Cryptococcus gatii from C. gatii- positive plant and soil samples could lead to the development of new antifungals (Mayer and Kronstad, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…A major limitation in this endeavor is that very few C. albicans strains are available for study from non-animal sources. The few isolates that have been obtained were from a broad range of sources (van Uden et al , 1956; Di Menna, 1958; Lachance et al , 2011; Robinson et al , 2016), and general environmental sampling for fungal pathogens can be challenging (Gerstein and Nielsen, 2017). In the future, the targeting of old trees could lead to improved environmental sampling success.…”

Section: Discussionmentioning

confidence: 99%

“…Many species of yeast live on trees, including other Candida species (Maganti et al , 2011; Charron et al , 2014; Sylvester et al , 2015) and woodlands represent the ancestral habitat for Saccharomyces species (Eberlein et al , 2015). Forests may also be an ancestral habitat and reservoir for fungal pathogens that infect humans such as Cryptococcus neoformans and Cryptococcus gattii (May et al , 2016; Gerstein and Nielsen, 2017). The isolation of C. albicans from plants (van Uden et al , 1956; Di Menna, 1958; Lachance et al , 2011; Robinson et al , 2016) raises the question of whether C. albicans is truly an obligate commensal of warm-blooded animals.…”

Section: Introductionmentioning

confidence: 99%

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Diverse lineages ofCandida albicanslive on old oaks

Bensasson

Dicks

Ludwig

et al. 2018

Preprint

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The human pathogen, Candida albicans, is considered an obligate commensal of animals, 1 yet it is occasionally isolated from trees, shrubs and grass. We generated deep genome 2 sequence data for three strains of C. albicans that we isolated from oak trees in an ancient 3 wood-pasture, and compared these to the genomes of the type strain and 21 other clinical 4 strains. C. albicans strains from oak are similar to clinical C. albicans in that they are 5 predominantly diploid and can become naturally homozygous at the mating locus through 6 whole-chromosome loss of heterozygosity (LOH). LOH regions in all genomes arose re-7 cently suggesting that LOH mutations usually occur transiently in C. albicans populations. 8Oak strains differed from clinical strains in showing less LOH, and higher levels of het-9 erozygosity genome-wide. Using phylogenomic analyses, in silico chromosome painting, 10 and comparisons with thousands more C. albicans strains at seven loci, we show that each 11 oak strain is more closely related to strains from humans and other animals than to strains 12 from other oaks. Therefore, the isolation of C. albicans from oak is not easily explained as 13 contamination from a single animal source. The high heterozygosity of oak strains could 14 arise as a result of reduced mitotic recombination in asexual lineages, recent parasexual 15 reproduction or because of natural selection. Regardless of mechanism, the diversity of C. 16 albicans on oaks implies that they have lived in this environment long enough for genetic 17 differences from clinical strains to arise. 18 Word count: 239 19

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Diverse lineages ofCandida albicanslive on old oaks

Bensasson

Dicks

Ludwig

et al. 2018

Preprint

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“…To the point, the laccase enzyme can be used to produce melanin from phenolic substrates found in the environment [75]. Production of melanin is reported to aid cells during the daytime to withstand ultraviolet (UV) light [76] by capturing radiation energy from the sun and converting it to chemical energy [77]. This quality (melanisation) also helps other organisms to harvest thermal radiation in vents found in the deep, dark ocean [77] or in the case of cryptococcal cells, when colonising the "dark" spaces of mammalian host bodies [78].…”

Section: Thermotolerancementioning

confidence: 99%

Environmental Factors That Contribute to the Maintenance of Cryptococcus neoformans Pathogenesis

et al. 2020

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The ability of microorganisms to colonise and display an intracellular lifestyle within a host body increases their fitness to survive and avoid extinction. This host–pathogen association drives microbial evolution, as such organisms are under selective pressure and can become more pathogenic. Some of these microorganisms can quickly spread through the environment via transmission. The non-transmittable fungal pathogens, such as Cryptococcus, probably return into the environment upon decomposition of the infected host. This review analyses whether re-entry of the pathogen into the environment causes restoration of its non-pathogenic state or whether environmental factors and parameters assist them in maintaining pathogenesis. Cryptococcus (C.) neoformans is therefore used as a model organism to evaluate the impact of environmental stress factors that aid the survival and pathogenesis of C. neoformans intracellularly and extracellularly.

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confidence: 99%

Identification of pathogen genomic differences that impact human immune response and disease duringCryptococcus neoformansinfection

Gerstein

Jackson

McDonald

et al. 2019

Preprint

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1 2Patient outcomes during infection are due to a complex interplay between the quality of medical 3 care, host immunity factors, and the infecting pathogen's characteristics. To probe the influence 4 of pathogen genotype on human immune response and disease, we examined Cryptococcus 5 neoformans isolates collected during the Cryptococcal Optimal ART Timing (COAT) trial in 6 Uganda. We measured human participants' immunologic phenotypes, meningitis disease 7 parameters, and survival. We compared this clinical data to whole genome sequences from 38 C. 8 neoformans isolates of the most frequently observed sequence type (ST) ST93 in our Ugandan 9 participant population, and an additional 18 strains from 9 other sequence types representing the 10 known genetic diversity within the Ugandan Cryptococcus clinical isolates. We focused our 11 analyses on 652 polymorphisms that: were variable among the ST93 genomes, were not in 12 centromeres or extreme telomeres, and were predicted to have a fitness effect. Logistic 13 regression and principal component analyses identified 40 candidate Cryptococcus genes and 3 14 hypothetical RNAs associated with human immunologic response or clinical parameters. We 15 infected mice with 17 available KN99α gene deletion strains for these candidate genes and found 16 that 35% (6/17) directly influenced murine survival. Four of the six gene deletions that impacted 17 murine survival were novel. Such bedside-to-bench translational research provides important 18 candidate genes for future studies on virulence-associated traits in human Cryptococcus 19 infections.Even with the best available care, mortality rates in cryptococcal meningitis range from 23 20-60%. Disease is often due to infection by the fungus Cryptococcus neoformans and involves a 24 complex interaction between the human host and the fungal pathogen. Although previous studies 25 have suggested genetic differences in the pathogen impact human disease, it has proven quite 26 difficult to identify the specific C. neoformans genes that impact the outcome of the human 27 infection. Here, we take advantage of a Ugandan patient cohort infected with closely related C. 28 neoformans strains to examine to role of pathogen genetic variants on several human disease 29 characteristics. Using a pathogen whole genome sequencing approach, we showed that 40 C. 30neoformans genes are associated with human disease. Surprisingly, many of these genes are 31 specific to Cryptococcus and have unknown functions. We also show deletion of these genes 32 alters disease in a mouse model of infection, confirming their role in disease. These findings are 33 particularly important because they are the first to identify C. neoformans genes associated with 34 human cryptococcal meningitis and lay the foundation for future studies that may lead to new 35 treatment strategies aimed at reducing patient mortality. 36 37 38Cryptococcus neoformans is the etiological agent of cryptococcal meningitis, the most 39 common brain infection in Sub-Saharan Africa, which enc...

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It's not all about us: evolution and maintenance ofCryptococcusvirulence requires selection outside the human host

Cited by 18 publications

References 104 publications

Diverse lineages ofCandida albicanslive on old oaks

Diverse lineages ofCandida albicanslive on old oaks

Environmental Factors That Contribute to the Maintenance of Cryptococcus neoformans Pathogenesis

Identification of pathogen genomic differences that impact human immune response and disease duringCryptococcus neoformansinfection

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