Mathematical modeling of the Candida albicans yeast to hyphal transition reveals novel control strategies
| Autor: | Reinhard Laubenbacher, Jorge Gómez Tejeda Zañudo, David Murrugarra, Anna Dongari-Bagtzoglou, David J. Wooten, Clarissa J. Nobile, Austin M. Perry, Réka Albert |
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| Přispěvatelé: | Thieffry, Denis |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Gene Expression Yeast and Fungal Models Pathology and Laboratory Medicine Biochemistry Mathematical Sciences Database and Informatics Methods Medical Conditions Models Candida albicans Morphogenesis Medicine and Health Sciences 2.1 Biological and endogenous factors 2.2 Factors relating to the physical environment Aetiology Biology (General) Candida Fungal Pathogens Ecology biology Systems Biology Fungal Diseases Eukaryota Biological Sciences Phenotype Corpus albicans Infectious Diseases Experimental Organism Systems Computational Theory and Mathematics Medical Microbiology Modeling and Simulation Pathogens Infection Sequence Analysis Network Analysis Research Article Computer and Information Sciences QH301-705.5 Bioinformatics Systems biology 030106 microbiology Hyphae Mycology Computational biology Research and Analysis Methods Network Motifs Models Biological Microbiology 03 medical and health sciences Cellular and Molecular Neuroscience Sequence Motif Analysis Information and Computing Sciences DNA-binding proteins Genetics Gene Regulation Microbial Pathogens Molecular Biology Gene Ecology Evolution Behavior and Systematics Phenotypic plasticity Mechanism (biology) Organisms Fungi Biology and Life Sciences Proteins Biological biology.organism_classification Yeast Regulatory Proteins Yeast Infections 030104 developmental biology Animal Studies Transcription Factors |
| Zdroj: | PLoS computational biology, vol 17, iss 3 PLoS Computational Biology, Vol 17, Iss 3, p e1008690 (2021) PLoS Computational Biology |
| Popis: | 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. Author summary Candida albicans is a pathogenic organism that commonly causes infection in humans, particularly in immunocompromised individuals, and patients in hospitals. A key mechanism mediating its infectiousness is a morphological change from single yeast cells into branching cell collectives called hyphae. C. albicans cells undergo this transition in response to multiple environmental signals, including pH, temperature, serum levels, or other molecules. Understanding how the cells process these environmental signals is critical to understanding how C. albicans adapts to thrive in human hosts. Here, we built and analyzed a mathematical model of the C. albicans yeast to hyphal transition, integrating multiple environmental factors and regulatory mechanisms. 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. We probed this model to identify interventional control strategies that can block the transition. We experimentally validate two of these control predictions: deletion of the transcription factor UME6, and deletion of the histone deacetylase HDA1. This model can be used to identify alternative hypotheses, enabling progress toward a systems biology understanding of C. albicans morphological changes. |
| Databáze: | OpenAIRE |
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