Stress-Induced Phenotypic Switching inCandida albicans

Abstract

Candida albicans is both a common commensal and an opportunistic pathogen, being a prevalent cause of mucosal and systemic infections in humans. Phenotypic switching between white and opaque forms is a reversible transition that influences virulence, mating behavior, and biofilm formation. In this work, we show that a wide range of factors induces high rates of switching from white to opaque. These factors include different forms of environmental stimuli such as genotoxic and oxidative stress, as well as intrinsic factors such as mutations in DNA repair genes. We propose that these factors increase switching to the opaque phase via a common mechanism-inhibition of cell growth. To confirm this hypothesis, growth rates were artificially manipulated by varying expression of the CLB4 cyclin gene; slowing cell growth by depleting CLB4 resulted in a concomitant increase in white-opaque switching. Furthermore, two clinical isolates of C. albicans, P37005 and L26, were found to naturally exhibit both slow growth and high rates of white-opaque switching. Notably, suppression of the slow growth phenotype suppressed hyperswitching in the P37005 isolate. Based on the sensitivity of the switch to levels of the master regulator Wor1, we propose a model for how changes in cellular growth modulate white-opaque switching frequencies.

A Novel Function for Hog1 Stress-Activated Protein Kinase in Controlling White-Opaque Switching and Mating in Candida albicans

“…albicans Hog1 SAPK is activated by many environmental cues, including osmotic and oxidative stimuli, heavy metal, glucose, and cationic peptides (45,(49)(50)(51). Two of them, oxidativestress levels and glucose concentrations, have been reported to be involved in opaque-cell formation and its stability (32,34,52). Our studies highlighted that deletion of HOG1 led to switching of white cells to the opaque state on SC and NAG media.…”

“…In regard to white-opaque switching, several stresses have been found to promote the switch from white to opaque (32)(33)(34). We therefore hypothesized that the Hog1 SAPK pathway of C. albicans could be involved in regulating this phenotypic transition.…”

“…This network is also controlled by the a1/␣2 complex which is produced in a/␣ heterozygous cells and which represses opaque-cell formation (30), although a recent study showed that some clinical a/␣ cells have the ability to switch to opaque under certain culture conditions (31). Several environmental factors, including CO 2 , temperature, oxidative stress, Nacetylglucosamine (NAG), and growth rate, also regulate whiteopaque switching (32)(33)(34), suggesting that the transition between white and opaque cells is extremely sensitive to external signals and dependent on the expression levels of the master regulator Wor1.…”

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

“…Each cell type is heritable for many generations, with multiple feedback loops regulating their stability. While switching appears largely stochastic, environmental cues influence the frequency of switching (3).…”

Evolution of Mating within the Candida parapsilosis Species Group

“…This circuit results in high levels of Efg1 in white cells and of Wor1 in opaque cells (79). The white/opaque switch is also regulated by many environmental stimuli, such as temperature (47), oxygen and carbon dioxide concentrations (27,58), and genotoxic and oxidative stress (1). Opaque cells are more stable at low temperatures, which favors mating on the surface of the skin (21,35).…”