Trimorphic stepping stones pave the way to fungal virulence

Bastidas, Robert J.; Heitman, Joseph

doi:10.1073/pnas.0811994106

Cited by 49 publications

(35 citation statements)

References 25 publications

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“…These results strongly suggest that a common transcriptional mechanism specifies the shift from yeast to pseudohyphal to hyphal morphology in a dosage-dependent manner and argue against models in which pseudohyphal and hyphal growth is determined by distinct genetic mechanisms. In addition, these results suggest that in the case of Candida species, morphology may have evolved in a stepwise fashion from yeast to pseudohyphae to hyphae (7). Consistent with this hypothesis, while many Candida species are capable of forming yeast and pseudohyphae, only three species, which are phylogenetically closely related (Candida tropicalis, C. dubliniensis, and C. albicans), are known to form hyphae as well (39,94,135) (Table 2).…”

Section: Evolution Of Yeast Pseudohyphal and Hyphal Morphologiessupporting

confidence: 54%

Coevolution of Morphology and Virulence in Candida Species

2011

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Many of the major human fungal pathogens are known to undergo morphological changes, which in certain cases are associated with virulence. Although there has been an intense research focus on morphology in fungi, very little is known about how morphology evolved in conjunction with a variety of other virulence properties. However, several recent important discoveries, primarily in Candida species, are beginning to shed light on this important area and answer many longstanding questions. In this minireview, we first provide a description of the major fungal morphologies, as well as the roles of morphology and morphology-associated gene expression in virulence. Next, focusing largely on Candida species, we examine the evolutionary relationships among specific morphological forms. Finally, drawing on recent findings, we begin to address the question of how specific morphological changes came to be associated with virulence of Candida species during evolution.

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Section: Evolution Of Yeast Pseudohyphal and Hyphal Morphologiessupporting

confidence: 54%

Coevolution of Morphology and Virulence in Candida Species

2011

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“…Hyphal forms are responsible for host recognition and also allow some pathogenic fungi to invade host tissues and escape immune cell control (19). Although hyphal forms of C. neoformans have not been commonly observed in host tissues (20), our results suggest that differentiation into hyphae upon unisexual reproduction may be advantageous in an environment outside the host, enabling increased access to nutrients, as well as pathogen dispersal.…”

Section: Figmentioning

confidence: 73%

Unisexual Reproduction Enhances Fungal Competitiveness by Promoting Habitat Exploration via Hyphal Growth and Sporulation

2013

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Unisexual reproduction is a novel homothallic sexual cycle recently discovered in both ascomycetous and basidiomycetous pathogenic fungi. It is a form of selfing that induces the yeast-to-hyphal dimorphic transition in isolates of the ␣ mating type of the human fungal pathogen Cryptococcus neoformans. Unisexual reproduction may benefit the pathogen by facilitating sexual reproduction in the absence of the opposite a mating type and by generating infectious propagules called basidiospores. Here, we report an independent potential selective advantage of unisexual reproduction beyond genetic exchange and recombination. We competed a wild-type strain capable of undergoing unisexual reproduction with mutants defective in this developmental pathway and found that unisexual reproduction provides a considerable dispersal advantage through hyphal growth and sporulation. Our results show that unisexual reproduction may serve to facilitate access to both nutrients and potential mating partners and may provide a means to maintain the capacity for dimorphic transitions in the environment. Sexual reproduction is pervasive and yet has established costs, including the time and energy devoted to locating a mate. A limited availability of mating partners of the opposite sex may further exacerbate this cost. The human fungal pathogen Cryptococcus neoformans illustrates this dilemma because its populations predominantly contain isolates of the ␣ mating type and few, if any, of the a mating type, restricting opportunities for conventional a-␣ opposite-sex mating (1, 2, 3). C. neoformans may overcome this barrier in part by undergoing unisexual reproduction-an alternative mode of sexual cycle involving cells of only one mating type, most commonly ␣ (4). Unisexual reproduction can confer benefits by generating adaptive genotypic diversity through recombination and by producing spore progeny that are readily dispersed aerially and inhaled as infectious propagules. Here, we report a novel way in which unisexual reproduction benefits C. neoformans, involving hyphal development to promote foraging and increased access to nutrients and facilitating the dispersal of spores.C. neoformans grows asexually as a budding yeast but differentiates into hyphae upon unisexual reproduction during solo culture of self-fertile isolates on appropriate growth media (4). Unisexual reproduction involves the formation of an extensive monokaryotic mycelium and terminal fruiting structures called basidia wherein meiosis occurs, and long chains of meiotic spores decorate the outer surface of the basidia (5). Components of a pheromone-responsive mitogen-activated protein kinase (MAPK) pathway are responsible for the yeast-to-hypha transition, and the absence of key elements, including the protein kinase Ste7 or the transcription factor Mat2, blocks unisexual reproduction and traps C. neoformans in the yeast form (6,7,8). While a functional MAPK pathway is necessary for morphological differentiation, the meiotic machinery, including Dmc1 and Spo11, is essential f...

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“…C. albicans is the most common human fungal pathogen and is able to switch back and forth from yeast to hyphal growth. This revertible morphogenetic switch plays a key role in the virulence of C. albicans (8)(9)(10). C. albicans and C. dubliniensis are phylogenetically closely related, sharing a polymorphic and obligatory diploid nature (11).…”

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confidence: 99%

Antifungal Application of Nonantifungal Drugs

Stylianou

Kulesskiy

Lopes

et al. 2014

Antimicrob Agents Chemother

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cCandida species are the cause of 60% of all mycoses in immunosuppressed individuals, leading to ϳ150,000 deaths annually due to systemic infections, whereas the current antifungal therapies either have toxic side effects or are insufficiently efficient. We performed a screening of two compound libraries, the Enzo and the Institute for Molecular Medicine Finland (FIMM) oncology collection library, for anti-Candida activity based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. From a total of 844 drugs, 26 agents showed activity against Candida albicans. Of those, 12 were standard antifungal drugs (SADs) and 7 were off-target drugs previously reported to be active against Candida spp. The remaining 7 offtarget drugs, amonafide, tosedostat, megestrol acetate, melengestrol acetate, stanozolol, trifluperidol, and haloperidol, were identified with this screen. The anti-Candida activities of the new agents were investigated by three individual assays using optical density, ATP levels, and microscopy. The antifungal activities of these drugs were comparable to those of the SADs found in the screen. The aminopeptidase inhibitor tosedostat, which is currently in a clinical trial phase for anticancer therapy, displayed a broad antifungal activity against different Candida spp., including Candida glabrata. Thus, this screen reveals agents that were previously unknown to be anti-Candida agents, which allows for the design of novel therapies against invasive candidiasis.

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Trimorphic stepping stones pave the way to fungal virulence

Cited by 49 publications

References 25 publications

Coevolution of Morphology and Virulence in Candida Species

Coevolution of Morphology and Virulence in Candida Species

Unisexual Reproduction Enhances Fungal Competitiveness by Promoting Habitat Exploration via Hyphal Growth and Sporulation

Antifungal Application of Nonantifungal Drugs

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