Role of
            <i>AFR1</i>
            , an ABC Transporter-Encoding Gene, in the In Vivo Response to Fluconazole and Virulence of
            <i>Cryptococcus neoformans</i>

Sanguinetti, Maurizio; Posteraro, Brunella; Sorda, Marilena La; Torelli, Riccardo; Fiori, Barbara; Santangelo, Rosaria; Delogu, Giovanni; Fadda, Giovanni

doi:10.1128/iai.74.2.1352-1359.2006

Cited by 109 publications

(106 citation statements)

References 43 publications

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“…In vivo data from a mouse model of infection support the hypothesis that AFR1 is important for virulence and drug resistance (508). A strain of C. neoformans overexpressing AFR1 had significantly increased virulence, and an afr1 mutant exhibited increased sensitivity to fluconazole (508). Finally, AFR1 also seems to have important roles in modulating the host immune response.…”

Section: Upregulation Of Multidrug Transportersmentioning

confidence: 77%

“…Fluconazole-resistant mutants generated in vitro through the The disruption of AFR1 enhanced susceptibility to fluconazole, and the complementation of the gene restored resistance (465). In vivo data from a mouse model of infection support the hypothesis that AFR1 is important for virulence and drug resistance (508). A strain of C. neoformans overexpressing AFR1 had significantly increased virulence, and an afr1 mutant exhibited increased sensitivity to fluconazole (508).…”

Section: Upregulation Of Multidrug Transportersmentioning

confidence: 79%

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Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

489

547

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SUMMARY Pathogenic fungi have become a leading cause of human mortality due to the increasing frequency of fungal infections in immunocompromised populations and the limited armamentarium of clinically useful antifungal drugs. Candida albicans , Cryptococcus neoformans , and Aspergillus fumigatus are the leading causes of opportunistic fungal infections. In these diverse pathogenic fungi, complex signal transduction cascades are critical for sensing environmental changes and mediating appropriate cellular responses. For C. albicans , several environmental cues regulate a morphogenetic switch from yeast to filamentous growth, a reversible transition important for virulence. Many of the signaling cascades regulating morphogenesis are also required for cells to adapt and survive the cellular stresses imposed by antifungal drugs. Many of these signaling networks are conserved in C. neoformans and A. fumigatus , which undergo distinct morphogenetic programs during specific phases of their life cycles. Furthermore, the key mechanisms of fungal drug resistance, including alterations of the drug target, overexpression of drug efflux transporters, and alteration of cellular stress responses, are conserved between these species. This review focuses on the circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence. Although the three human-pathogenic fungi highlighted in this review are those most frequently encountered in the clinic, they represent a minute fraction of fungal diversity. Exploration of the conservation and divergence of core signal transduction pathways across C. albicans , C. neoformans , and A. fumigatus provides a foundation for the study of a broader diversity of pathogenic fungi and a platform for the development of new therapeutic strategies for fungal disease.

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Section: Upregulation Of Multidrug Transportersmentioning

confidence: 77%

Section: Upregulation Of Multidrug Transportersmentioning

confidence: 79%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

489

547

View full text Add to dashboard Cite

show abstract

“…Upregulation of the ATP-binding cassette transporter-encoding gene AFR1 in C. neoformans was associated with resistance to fluconazole in vitro and in mice with systemic cryptococcosis (380,383).…”

Section: Mechanisms Of Azole Resistance In C Gattiimentioning

confidence: 98%

“…A few studies have examined the roles of the cryptococcal ERG11 gene and of the ATP-binding cassette transporters in resistance in C. neoformans (377)(378)(379)(380); whether these observations are applicable to C. gattii are uncertain. Mutations in, or overexpression of, the ERG11 gene, encoding the azole target lanosterol 14-␣ demethylase, and overexpression of one or more plasma membrane proteins that pump azoles out of the cell are well recognized mechanisms by which fungi acquire resistance to azoles (379).…”

Section: Mechanisms Of Azole Resistance In C Gattiimentioning

confidence: 99%

“…Enhanced activity of plasma membrane azole efflux pumps, which has been associated with azole resistance of C. neoformans, has not yet been studied in C. gattii (380,382). Upregulation of the ATP-binding cassette transporter-encoding gene AFR1 in C. neoformans was associated with resistance to fluconazole in vitro and in mice with systemic cryptococcosis (380,383).…”

Section: Mechanisms Of Azole Resistance In C Gattiimentioning

confidence: 99%

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Cryptococcus gattii Infections

2014

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SUMMARY Understanding of the taxonomy and phylogeny of Cryptococcus gattii has been advanced by modern molecular techniques. C. gattii probably diverged from Cryptococcus neoformans between 16 million and 160 million years ago, depending on the dating methods applied, and maintains diversity by recombining in nature. South America is the likely source of the virulent C. gattii VGII molecular types that have emerged in North America. C. gattii shares major virulence determinants with C. neoformans , although genomic and transcriptomic studies revealed that despite similar genomes, the VGIIa and VGIIb subtypes employ very different transcriptional circuits and manifest differences in virulence phenotypes. Preliminary evidence suggests that C. gattii VGII causes severe lung disease and death without dissemination, whereas C. neoformans disseminates readily to the central nervous system (CNS) and causes death from meningoencephalitis. Overall, currently available data indicate that the C. gattii VGI, VGII, and VGIII molecular types more commonly affect nonimmunocompromised hosts, in contrast to VGIV. New, rapid, cheap diagnostic tests and imaging modalities are assisting early diagnosis and enabling better outcomes of cerebral cryptococcosis. Complications of CNS infection include increased intracranial pressure, severe neurological sequelae, and development of immune reconstitution syndrome, although the mortality rate is low. C. gattii VGII isolates may exhibit higher fluconazole MICs than other genotypes. Optimal therapeutic regimens are yet to be determined; in most cases, initial therapy with amphotericin B and 5-flucytosine is recommended.

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Protein‐facilitated transport of hydrophobic molecules across the yeast plasma membrane

2019

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In yeasts, the plasma membrane forms the barrier that protects the cell from the outside world, but also gathers and keeps valuable compounds inside. Although it is often suggested that hydrophobic molecules surpass this checkpoint by simple diffusion, it now becomes evident that protein‐facilitated transport mechanisms allow for selective import and export of triglycerides, fatty acids, alkanes, and sterols in yeasts. During biomass production, hydrophobic carbon sources enter and exit the cell efficiently in a strictly regulated manner that helps avoid toxicity. Furthermore, various molecules, such as yeast pheromones, secondary metabolites and xenobiotics, are exported to ensure cell–cell communication, or increase chances of survival. This review summarizes the current knowledge on how hydrophobic compounds interact with protein‐facilitated transport systems on the plasma membrane and how selective import and export across the yeast plasma membrane is achieved. Both the model organism Saccharomyces cerevisiae, as well as unconventional yeasts are discussed.

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Role of AFR1 , an ABC Transporter-Encoding Gene, in the In Vivo Response to Fluconazole and Virulence of Cryptococcus neoformans

Cited by 109 publications

References 43 publications

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Cryptococcus gattii Infections

Protein‐facilitated transport of hydrophobic molecules across the yeast plasma membrane

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