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Review

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Rebecca S. Shapiro, Nicole Robbins, Leah E. Cowen
Rebecca S. Shapiro
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
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Nicole Robbins
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
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Leah E. Cowen
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
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  • For correspondence: leah.cowen@utoronto.ca
DOI: 10.1128/MMBR.00045-10
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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.

  • Copyright © 2011, American Society for Microbiology
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Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease
Rebecca S. Shapiro, Nicole Robbins, Leah E. Cowen
Microbiology and Molecular Biology Reviews Jun 2011, 75 (2) 213-267; DOI: 10.1128/MMBR.00045-10

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Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease
Rebecca S. Shapiro, Nicole Robbins, Leah E. Cowen
Microbiology and Molecular Biology Reviews Jun 2011, 75 (2) 213-267; DOI: 10.1128/MMBR.00045-10
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  • Top
  • Article
    • SUMMARY
    • INTRODUCTION
    • WHAT IS ANTIFUNGAL DRUG RESISTANCE?
    • MECHANISM OF ACTION OF ANTIFUNGAL DRUGS
    • CANDIDA ALBICANS
    • INTRODUCTION TO CANDIDA ALBICANS MORPHOGENESIS: YEAST, PSEUDOHYPHAE, AND HYPHAE
    • CANDIDA ALBICANS DRUG RESISTANCE: THE AZOLES
    • CANDIDA ALBICANS DRUG RESISTANCE: THE POLYENES
    • CANDIDA ALBICANS DRUG RESISTANCE: THE ECHINOCANDINS
    • CONNECTIONS BETWEEN MORPHOGENESIS AND ANTIFUNGAL DRUG RESISTANCE IN CANDIDA ALBICANS
    • CRYPTOCOCCUS NEOFORMANS
    • INTRODUCTION TO CRYPTOCOCCUS NEOFORMANS MORPHOGENESIS
    • CRYPTOCOCCUS NEOFORMANS DRUG RESISTANCE: THE AZOLES
    • CRYPTOCOCCUS NEOFORMANS DRUG RESISTANCE: THE POLYENES
    • CRYPTOCOCCUS NEOFORMANS DRUG RESISTANCE: THE ECHINOCANDINS
    • CRYPTOCOCCUS NEOFORMANS DRUG RESISTANCE: FLUDIOXONIL
    • ASPERGILLUS FUMIGATUS
    • INTRODUCTION TO ASPERGILLUS FUMIGATUS MORPHOGENESIS
    • ASPERGILLUS FUMIGATUS DRUG RESISTANCE: THE AZOLES
    • ASPERGILLUS FUMIGATUS DRUG RESISTANCE: THE POLYENES
    • ASPERGILLUS FUMIGATUS DRUG RESISTANCE: THE ECHINOCANDINS
    • CONNECTIONS BETWEEN MORPHOGENESIS AND ANTIFUNGAL DRUG RESISTANCE IN ASPERGILLUS FUMIGATUS
    • CONCLUSION
    • ACKNOWLEDGMENTS
    • REFERENCES
    • Author Bios
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