Candida albicans White and Opaque Cells Undergo Distinct Programs of Filamentous Growth

Haoyu Si,Matthew P Hirakawa,Richard J Bennett,Aaron D Hernday,Alexander D Johnson,Aaron P Mitchell

doi:10.1371/journal.ppat.1003210

Haoyu Si, Matthew P Hirakawa + Show 4 more

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https://doi.org/10.1371/journal.ppat.1003210

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Abstract

The ability to switch between yeast and filamentous forms is central to Candida albicans biology. The yeast-hyphal transition is implicated in adherence, tissue invasion, biofilm formation, phagocyte escape, and pathogenesis. A second form of morphological plasticity in C. albicans involves epigenetic switching between white and opaque forms, and these two states exhibit marked differences in their ability to undergo filamentation. In particular, filamentous growth in white cells occurs in response to a number of environmental conditions, including serum, high temperature, neutral pH, and nutrient starvation, whereas none of these stimuli induce opaque filamentation. Significantly, however, we demonstrate that opaque cells can undergo efficient filamentation but do so in response to distinct environmental cues from those that elicit filamentous growth in white cells. Growth of opaque cells in several environments, including low phosphate medium and sorbitol medium, induced extensive filamentous growth, while white cells did not form filaments under these conditions. Furthermore, while white cell filamentation is often enhanced at elevated temperatures such as 37°C, opaque cell filamentation was optimal at 25°C and was inhibited by higher temperatures. Genetic dissection of the opaque filamentation pathway revealed overlapping regulation with the filamentous program in white cells, including key roles for the transcription factors EFG1, UME6, NRG1 and RFG1. Gene expression profiles of filamentous white and opaque cells were also compared and revealed only limited overlap between these programs, although UME6 was induced in both white and opaque cells consistent with its role as master regulator of filamentation. Taken together, these studies establish that a program of filamentation exists in opaque cells. Furthermore, this program regulates a distinct set of genes and is under different environmental controls from those operating in white cells.

Highlights

Morphological plasticity is key to the lifestyle of fungal pathogens such as Candida albicans, the most frequently isolated human fungal pathogen
Perhaps the best-studied aspect of C. albicans biology is the transition between the single-celled yeast form and the multicellular filamentous form
We further show that opaque cells can undergo filamentation, but that they do so in response to different environmental cues than those of white cells

Summary

Introduction

Morphological plasticity is key to the lifestyle of fungal pathogens such as Candida albicans, the most frequently isolated human fungal pathogen. The best-studied morphological switch in C. albicans is the transition between yeast and true hyphae or pseudohyphae (filamentous forms). Pseudohyphal cells are highly branched and consist of ellipsoidal cells with constrictions at the septa. Hyphal cells are less branched, have parallel sides, and lack constrictions at the septa [1,2]. The yeast-hyphal switch regulates C. albicans pathogenesis, as hyphal forms adhere to and invade epithelial cells during mucosal infections, resulting in extensive damage to host cells [2]. The hyphal form is important for virulence in systemic models of disease, it is not clear if the hyphal morphology per se or genes coregulated with the morphological transition are critical for virulence [2]

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