Open AccessMathematical modeling of the Candida albicans yeast to hyphal transition reveals novel control strategies
Author(s) -
David J. Wooten,
Jorge Gómez Tejeda Zañudo,
David Murrugarra,
Austin M. Perry,
Anna Dongari-Bagtzoglou,
Reinhard Laubenbacher,
Clarissa J. Nobile,
Réka Albert
Publication year - 2021
Publication title -
plos computational biology/plos computational biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.628
H-Index - 182
eISSN - 1553-7358
pISSN - 1553-734X
DOI - 10.1371/journal.pcbi.1008690
Subject(s) - candida albicans , biology , yeast , corpus albicans , phenotype , fungal protein , computational biology , model organism , transition (genetics) , transcription factor , microbiology and biotechnology , hypha , genetics , gene , saccharomyces cerevisiae
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.