Abstract
Candida albicans, an opportunistic fungal pathogen, is a significant cause of human infections, particularly in immunocompromised individuals. Phenotypic plasticity between two morphological phenotypes, yeast and hyphae, is a key mechanism by which C. albicans can thrive in many microenvironments and cause disease in the host. Understanding the decision points and key driver genes controlling this important transition and how these genes respond to different environmental signals is critical to understanding how C. albicans causes infections in the host. Here we build and analyze a Boolean dynamical model of the C. albicans yeast to hyphal transition, integrating multiple environmental factors and regulatory mechanisms. We validate the model by a systematic comparison to prior experiments, which led to agreement in 17 out of 22 cases. The discrepancies motivate alternative hypotheses that are testable by follow-up experiments. Analysis of this model revealed two time-constrained windows of opportunity that must be met for the complete transition from the yeast to hyphal phenotype, as well as control strategies that can robustly prevent this transition. We experimentally validate two of these control predictions in C. albicans strains lacking the transcription factor UME6 and the histone deacetylase HDA1, respectively. This model will serve as a strong base from which to develop a systems biology understanding of C. albicans morphogenesis.
Highlights
Candida albicans is a pleiomorphic, opportunistic fungal pathogen and an important cause of both superficial and systemic infections in humans, in immunocompromised individuals
External signals initiate the downregulation of NRG1 transcription, while Nrg1 protein is prevented from binding to the promoters of hyphal-associated genes (HAGs) by histone deacetylases (HDACs) such as Hda1
As a starting point to building a model of the intracellular network that controls the yeast to hyphal transition (YHT), we focused on the most studied transcription factors that mediate hyphal initiation (Efg1 and Brg1), hyphal maintenance (Ume6), or inhibit these processes (Nrg1)
Summary
Candida albicans is a pleiomorphic, opportunistic fungal pathogen and an important cause of both superficial and systemic infections in humans, in immunocompromised individuals. The yeast to hyphal transition is regulated by many well-studied intracellular pathways that respond to external signals such as neutral or alkaline pH (pH > 6), farnesol levels, and temperature These pathways converge on a handful of key transcription factors, defined as sequence-specific DNA-binding proteins, which regulate the transcription of hyphal-associated genes (HAGs). Epigenetic effects such as histone acetylation events at the promoters of HAGs play important roles in the regulation of the expression of HAGs. The key negative regulator of the transcription of HAGs is Nrg. External signals initiate the downregulation of NRG1 transcription, while Nrg protein is prevented from binding to the promoters of HAGs by histone deacetylases (HDACs) such as Hda
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