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      White-Opaque Switching in Natural MTLa/α Isolates of Candida albicans: Evolutionary Implications for Roles in Host Adaptation, Pathogenesis, and Sex

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          Abstract

          All Mating Type Locus strain types of Candida albicans show white-opaque switching competency, not just MTL homozygotes, which allows them to adapt better to environmental changes.

          Abstract

          Phenotypic transitions play critical roles in host adaptation, virulence, and sexual reproduction in pathogenic fungi. A minority of natural isolates of Candida albicans, which are homozygous at the mating type locus ( MTL, a/ a or α/α), are known to be able to switch between two distinct cell types: white and opaque. It is puzzling that white-opaque switching has never been observed in the majority of natural C. albicans strains that have heterozygous MTL genotypes ( a/α), given that they contain all of the opaque-specific genes essential for switching. Here we report the discovery of white-opaque switching in a number of natural a/α strains of C. albicans under a condition mimicking aspects of the host environment. The optimal condition for white-to-opaque switching in a/α strains of C. albicans is to use N-acetylglucosamine (GlcNAc) as the sole carbon source and to incubate the cells in 5% CO 2. Although the induction of white-to-opaque switching in a/α strains of C. albicans is not as robust as in MTL homozygotes in response to GlcNAc and CO 2, opaque cells of a/α strains exhibit similar features of cellular and colony morphology to their MTL homozygous counterparts. Like MTL homozygotes, white and opaque cells of a/α strains differ in their behavior in different mouse infection models. We have further demonstrated that the transcriptional regulators Rfg1, Brg1, and Efg1 are involved in the regulation of white-to-opaque switching in a/α strains. We propose that the integration of multiple environmental cues and the activation and inactivation of a set of transcriptional regulators controls the expression of the master switching regulator WOR1, which determines the final fate of the cell type in C. albicans. Our discovery of white-opaque switching in the majority of natural a/α strains of C. albicans emphasizes its widespread nature and importance in host adaptation, pathogenesis, and parasexual reproduction.

          Author Summary

          Phenotypic transitions enable fungal pathogens to better adapt to their ever-changing environments. Approximately 10% of natural Candida albicans strains, which are homozygous at the mating type locus ( MTL, a/ a and α/α), can switch between two distinguishable morphological forms: white and opaque. The two cell types differ in a number of biological aspects including virulence, susceptibility to host immune attacks, and mating competency. Here, we demonstrate that white-opaque switching competency is not restricted to the MTL homozygous strains, but is a general characteristic of all MTL strain types of C. albicans ( a/ a, α/α, and a/α). Two host environmental cues, N-acetylglucosamine and CO 2, promote white-to-opaque switching and stabilize the opaque phenotype. Thus, although switching is normally blocked in a/α cells, this block can be overcome through specific environmental changes. We further show that three transcriptional regulators (Rfg1, Brg1, and Efg1) help to regulate white-opaque switching in MTL heterozygotes of C. albicans. This study generalizes white-opaque switching to strains with all mating-type configurations and emphasizes its importance in host adaptation, pathogenesis, and parasexual reproduction.

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          Author and article information

          Contributors
          Role: Academic Editor
          Journal
          PLoS Biol
          PLoS Biol
          plos
          plosbiol
          PLoS Biology
          Public Library of Science (San Francisco, USA )
          1544-9173
          1545-7885
          March 2013
          March 2013
          26 March 2013
          : 11
          : 3
          : e1001525
          Affiliations
          [1 ]State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
          [2 ]University of Chinese Academy of Sciences, Beijing, China
          [3 ]Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, United States of America
          [4 ]Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
          Duke University Medical Center, United States of America
          Author notes

          The authors have declared that no competing interests exist.

          The author(s) have made the following declarations about their contributions: Conceived and designed the experiments: JX LT CJN FB GH. Performed the experiments: JX LT CJN YT GG YS CC ADH GH. Analyzed the data: JX LT CJN YT GG YS CC ADH ADJ LZ FB GH. Contributed reagents/materials/analysis tools: JX LT CJN YT GG YS CC ADH ADJ LZ FB GH. Wrote the paper: JX LT CJN YT GG YS CC ADH ADJ LZ FB GH.

          Article
          PBIOLOGY-D-12-04944
          10.1371/journal.pbio.1001525
          3608550
          23555196
          1433184c-286e-49d6-9abb-152c5a6f30ff
          Copyright @ 2013

          This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

          History
          : 12 December 2012
          : 14 February 2013
          Page count
          Pages: 12
          Funding
          This work was supported by the “100 Talent Program” grant from the Chinese Academy of Sciences and grant 31170086 from the Chinese National Natural Science Foundation (to G.H.). F.B. was supported by grant 30825002 from the Chinese National Natural Science Foundation. C.J.N. was supported by NIH grant K99AI100896. C.J.N., A.D.H., and A.D.J. were supported by NIH grant R01AI049187. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
          Categories
          Research Article
          Biology
          Microbiology
          Mycology
          Fungal Physiology
          Yeast
          Medical Microbiology
          Microbial Pathogens

          Life sciences
          Life sciences

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