This Viewpoint was written in association with the 25th anniversary of the American Society for Clinical Investigation's (ASCI's) Stanley J. Korsmeyer Award, which honors the highest standards of ...scientific excellence, meritorious research, intellectual integrity, and the mentoring of future life-science researchers. In 2018, the award recognized Joseph Heitman (Figure 1), for his key contributions to our understanding of how eukaryotic microbial pathogens evolve, cause disease, and develop drug resistance and his discovery of TOR and FKBP12 as targets of the immunosuppressive chemotherapeutic drug rapamycin. Dr. Heitman has mentored numerous undergraduates, medical students, graduate students, and postdoctoral and medical fellows, many of whom have developed independent careers in medicine and basic biomedical research.
The National Institutes of Health (NIH) launched the medical scientist training program in 1964 to train physician-scientists as ambassadors between the disparate worlds of science and medicine. ...Scientists at this company discovered and developed cyclosporin as the gold-standard drug for organ transplant patients.
Sexual reproduction is critical for successful evolution of eukaryotic organisms in adaptation to changing environments. In the opportunistic human fungal pathogens, the Cryptococcus pathogenic ...species complex, C. neoformans primarily undergoes bisexual reproduction, while C. deneoformans undergoes both unisexual and bisexual reproduction. During both unisexual and bisexual cycles, a common set of genetic circuits regulates a yeast-to-hyphal morphological transition, that produces either monokaryotic or dikaryotic hyphae. As such, both the unisexual and bisexual cycles can generate genotypic and phenotypic diversity de novo. Despite the similarities between these two cycles, genetic and morphological differences exist, such as the absence of an opposite mating-type partner and monokaryotic instead of dikaryotic hyphae during C. deneoformans unisexual cycle. To better understand the similarities and differences between these modes of sexual reproduction, we focused on two cellular processes involved in sexual reproduction: cell-cell fusion and karyogamy. We identified orthologs of the plasma membrane fusion protein Prm1 and the nuclear membrane fusion protein Kar5 in both Cryptococcus species, and demonstrated their conserved roles in cell fusion and karyogamy during C. deneoformans α-α unisexual reproduction and C. deneoformans and C. neoformans a-α bisexual reproduction. Notably, karyogamy occurs inside the basidum during bisexual reproduction in C. neoformans, but often occurs earlier following cell fusion during bisexual reproduction in C. deneoformans. Characterization of these two genes also showed that cell fusion is dispensable for solo unisexual reproduction in C. deneoformans. The blastospores produced along hyphae during C. deneoformans unisexual reproduction are diploid, suggesting that diploidization occurs early during hyphal development, possibly through either an endoreplication pathway or cell fusion-independent karyogamy events. Taken together, our findings suggest distinct mating mechanisms for unisexual and bisexual reproduction in Cryptococcus, exemplifying distinct evolutionary trajectories within this pathogenic species complex.
The continuous emergence of antifungal drug resistance is a mounting concern for the treatment of fungal infections worldwide. While many pathogenic fungi exhibit some level of antifungal drug ...resistance, the identification of Candida auris has brought this phenomenon to the fore in recent years. C. auris exhibits resistance to all antifungal drugs used for treatment, and it does so at a very high rate, with more than 90% of isolates being resistant to at least one drug and roughly 4% being panresistant. However, the environmental factors driving this exceptionally high antifungal drug resistance remain unidentified. The presence of C. auris on stored apples that are treated with antifungals during storage suggests a possible route to selection of drug-resistant C. auris isolates that may have contributed to the evolution of this deadly pathogen. This study further suggests that the adage "an apple a day keeps the doctor away" may need to be revisited in light of the discovery of C. auris on the surface of apples.
Cryptococcus neoformans is a human fungal pathogen with a defined sexual cycle. Nutrient-limiting conditions and pheromones induce a dimorphic transition from unicellular yeast to multicellular ...hyphae and the production of infectious spores. Sexual reproduction involves cells of either opposite (bisexual) or one (unisexual) mating type. Bisexual and unisexual reproduction are governed by shared components of the conserved pheromone-sensing Cpk1 MAPK signal transduction cascade and by Mat2, the major transcriptional regulator of the pathway. However, the downstream targets of the pathway are largely unknown, and homology-based approaches have failed to yield downstream transcriptional regulators or other targets. In this study, we applied insertional mutagenesis via Agrobacterium tumefaciens transkingdom DNA delivery to identify mutants with unisexual reproduction defects. In addition to elements known to be involved in sexual development (Crg1, Ste7, Mat2, and Znf2), three key regulators of sexual development were identified by our screen: Znf3, Spo11, and Ubc5. Spo11 and Ubc5 promote sporulation during both bisexual and unisexual reproduction. Genetic and phenotypic analyses provide further evidence implicating both genes in the regulation of meiosis. Phenotypic analysis of sexual development showed that Znf3 is required for hyphal development during unisexual reproduction and also plays a central role during bisexual reproduction. Znf3 promotes cell fusion and pheromone production through a pathway parallel to and independent of the pheromone signaling cascade. Surprisingly, Znf3 participates in transposon silencing during unisexual reproduction and may serve as a link between RNAi silencing and sexual development. Our studies illustrate the power of unbiased genetic screens to reveal both novel and conserved circuits that operate sexual reproduction.
The environmentally ubiquitous fungus
is a primary cause of the emerging disease mucormycosis.
infection is notable for causing high morbidity and mortality, especially in immunosuppressed patients, ...while being inherently resistant to the majority of clinically available antifungal drugs. A new, RNA interference (RNAi)-dependent, and reversible epigenetic mechanism of antifungal resistance-epimutation-was recently discovered in
However, the effects of epimutation in a host-pathogen setting were unknown. We employed a systemic, intravenous murine model of
infection to elucidate the potential impact of epimutation
Infection with an epimutant strain resistant to the antifungal agents FK506 and rapamycin revealed that the epimutant-induced drug resistance was stable
in a variety of different organs and tissues. Reversion of the epimutant-induced drug resistance was observed to be more rapid in isolates from the brain than in isolates recovered from the liver, spleen, kidney, or lungs. Importantly, infection with a wild-type strain of
led to increased rates of epimutation after strains were recovered from organs and exposed to FK506 stress
Once again, this effect was more pronounced in strains recovered from the brain than from other organs. In summary, we report the rapid induction and reversion of RNAi-dependent drug resistance after
passage through a murine model, with pronounced impact in strains recovered from brain. Defining the role played by epimutation in drug resistance and infection advances our understanding of
and other fungal pathogens and may have implications for antifungal therapy.
The emerging fungal pathogen
causes a severe infection, mucormycosis, which leads to considerable morbidity and mortality. Treatment of
infection is challenging because
is inherently resistant to nearly all clinical antifungal agents. An RNAi-dependent and reversible mechanism of antifungal resistance, epimutation, was recently reported for
Epimutation has not been studied
, and it was unclear whether it would contribute to antifungal resistance observed clinically. We demonstrate that epimutation can both be induced and reverted after
passage through a mouse; rates of both induction and reversion are higher after brain infection than after infection of other organs (liver, spleen, kidneys, or lungs). Elucidating the roles played by epimutation in drug resistance and infection will improve our understanding of
and other fungal pathogens and may have implications for antifungal treatment.
The human fungal pathogen
is RNAi-deficient and lacks active transposons in its genome.
has regional centromeres that contain only transposon relics. To investigate the impact of centromere loss on ...the
genome, either centromere 9 or 10 was deleted. Deletion of either centromere resulted in neocentromere formation and interestingly, the genes covered by these neocentromeres maintained wild-type expression levels. In contrast to
∆ mutants,
∆ mutant strains exhibited growth defects and were aneuploid for chromosome 10. At an elevated growth temperature (37°C), the
∆ chromosome was found to have undergone fusion with another native chromosome in some isolates and this fusion restored wild-type growth. Following chromosomal fusion, the neocentromere was inactivated, and the native centromere of the fused chromosome served as the active centromere. The neocentromere formation and chromosomal fusion events observed in this study in
may be similar to events that triggered genomic changes within the
/
species complex and may contribute to speciation throughout the eukaryotic domain.
Sex in fungi Ni, Min; Feretzaki, Marianna; Sun, Sheng ...
Annual review of genetics,
01/2011, Letnik:
45
Journal Article
Recenzirano
Odprti dostop
Sexual reproduction enables genetic exchange in eukaryotic organisms as diverse as fungi, animals, plants, and ciliates. Given its ubiquity, sex is thought to have evolved once, possibly concomitant ...with or shortly after the origin of eukaryotic organisms themselves. The basic principles of sex are conserved, including ploidy changes, the formation of gametes via meiosis, mate recognition, and cell-cell fusion leading to the production of a zygote. Although the basic tenants are shared, sex determination and sexual reproduction occur in myriad forms throughout nature, including outbreeding systems with more than two mating types or sexes, unisexual selfing, and even examples in which organisms switch mating type. As robust and diverse genetic models, fungi provide insights into the molecular nature of sex, sexual specification, and evolution to advance our understanding of sexual reproduction and its impact throughout the eukaryotic tree of life.
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