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Zinc Cluster Transcription Factors Alter Virulence In Candida Albicans

Luca Issi, R. Farrer, Kelly Pastor, B. Landry, Toni Delorey, G. Bell, D. Thompson, C. Cuomo, Reeta P Rao
Published 2016 · Biology, Medicine

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Almost all humans are colonized with Candida albicans. However, in immunocompromised individuals, this benign commensal organism becomes a serious, life-threatening pathogen. Here, we describe and analyze the regulatory networks that modulate innate responses in the host niches. We identified Zcf15 and Zcf29, two Zinc Cluster transcription Factors (ZCF) that are required for C. albicans virulence. Previous sequence analysis of clinical C. albicans isolates from immunocompromised patients indicates that both ZCF genes diverged during clonal evolution. Using in vivo animal models, ex vivo cell culture methods, and in vitro sensitivity assays, we demonstrate that knockout mutants of both ZCF15 and ZCF29 are hypersensitive to reactive oxygen species (ROS), suggesting they help neutralize the host-derived ROS produced by phagocytes, as well as establish a sustained infection in vivo. Transcriptomic analysis of mutants under resting conditions where cells were not experiencing oxidative stress revealed a large network that control macro and micronutrient homeostasis, which likely contributes to overall pathogen fitness in host niches. Under oxidative stress, both transcription factors regulate a separate set of genes involved in detoxification of ROS and down-regulating ribosome biogenesis. ChIP-seq analysis, which reveals vastly different binding partners for each transcription factor (TF) before and after oxidative stress, further confirms these results. Furthermore, the absence of a dominant binding motif likely facilitates their mobility, and supports the notion that they represent a recent expansion of the ZCF family in the pathogenic Candida species. Our analyses provide a framework for understanding new aspects of the interface between C. albicans and host defense response, and extends our understanding of how complex cell behaviors are linked to the evolution of TFs.
This paper references
10.1016/j.cub.2010.06.031
Hierarchical Evolution of the Bacterial Sporulation Network
M. D. Hoon (2010)
10.1371/journal.pcbi.1003326
Practical Guidelines for the Comprehensive Analysis of ChIP-seq Data
T. Bailey (2013)
10.4161/viru.22700
The role of Candida albicans AP-1 protein against host derived ROS in in vivo models of infection
C. Jain (2013)
10.1093/bioinformatics/btp352
The Sequence Alignment/Map format and SAMtools
Heng Li (2009)
within the Arabidopsis circadian clock
10.1099/mic.0.064097-0
Shuttle vectors for facile gap repair cloning and integration into a neutral locus in Candida albicans.
M. Gerami-Nejad (2013)
The type II Ca2+/calmodulin
X. 1181 Ding (2014)
A pathogenesis assay
C. Jain (2009)
NADPH oxidase of human
M. 1185 Donini (2007)
10.1128/AAC.01467-10
Differential Requirement of the Transcription Factor Mcm1 for Activation of the Candida albicans Multidrug Efflux Pump MDR1 by Its Regulators Mrr1 and Cap1
Selene Mogavero (2011)
10.1111/mmi.13320
A Candida albicans regulator of disseminated infection operates primarily as a repressor and governs cell surface remodeling
Lena Böhm (2016)
A Candida albicans regulator
L. 1145 Bohm (2016)
10.1093/NAR/GKH340
MUSCLE: multiple sequence alignment with high accuracy and high throughput.
R. Edgar (2004)
Association of RAP1 binding sites
C. M. Moehle (1991)
10.1128/EC.00279-10
Candida albicans Als3, a Multifunctional Adhesin and Invasin
Y. Liu (2010)
Role of the Hog1
B. 1199 Enjalbert (2006)
10.1016/J.FGB.2006.11.006
The key enzyme in galactose metabolism, UDP-galactose-4-epimerase, affects cell-wall integrity and morphology in Candida albicans even in the absence of galactose.
Vijender Singh (2007)
10.1016/j.mib.2013.09.006
Candida albicans specializations for iron homeostasis: from commensalism to virulence.
S. Noble (2013)
10.1016/j.cell.2011.10.048
A Recently Evolved Transcriptional Network Controls Biofilm Development in Candida albicans
C. J. Nobile (2012)
10.1126/SCIENCE.1061320
Reciprocal Regulation Between TOC1 and LHY/CCA1 Within the Arabidopsis Circadian Clock
D. Alabadi (2001)
A phenotypic profile
O. R. 1218 Homann (2009)
10.1128/IAI.00860-08
Live Candida albicans Suppresses Production of Reactive Oxygen Species in Phagocytes
M. Wellington (2008)
10.1128/MCB.19.8.5393
Transcriptional Elements Involved in the Repression of Ribosomal Protein Synthesis
B. Li (1999)
Metabolism impacts upon
A. J. Brown (2014)
10.1016/0378-4274(95)03532-X
Toxicity of iron and hydrogen peroxide: the Fenton reaction.
C. Winterbourn (1995)
10.1128/JB.140.3.874-880.1979
Regulation of activity and synthesis of N-acetylglutamate synthase from Saccharomyces cerevisiae.
B. Wipe (1979)
10.4161/viru.22913
Candida albicans pathogenicity mechanisms
François L Mayer (2013)
10.1101/gr.146233.112
Arboretum: reconstruction and analysis of the evolutionary history of condition-specific transcriptional modules.
S. Roy (2013)
10.1002/pmic.201200228
Carbon source-induced reprogramming of the cell wall proteome and secretome modulates the adherence and drug resistance of the fungal pathogen Candida albicans
Iuliana V. Ene (2012)
10.1016/S0962-8924(98)01298-7
The control of filamentous differentiation and virulence in fungi.
H. Madhani (1998)
10.1093/bioinformatics/btp324
Fast and accurate short read alignment with Burrows–Wheeler transform
Heng Li (2009)
10.1371/journal.ppat.1002074
Candida albicans Infection of Caenorhabditis elegans Induces Antifungal Immune Defenses
R. Pukkila-Worley (2011)
The evolution of drug
C. B. Ford (2015)
Isolation of the MIG1 gene
O. Zaragoza (2000)
Hierarchical evolution
M. J. de Hoon (2010)
10.1128/EC.00236-07
Candida albicans Sfl1 Suppresses Flocculation and Filamentation
J. Bauer (2007)
10.1021/BI00424A003
Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate.
M. Marletta (1988)
10.1128/EC.00017-08
Carnitine-Dependent Transport of Acetyl Coenzyme A in Candida albicans Is Essential for Growth on Nonfermentable Carbon Sources and Contributes to Biofilm Formation
Karin Strijbis (2008)
ROS and innate immunity.
C. Kohchi (2009)
10.1128/EC.3.5.1076-1087.2004
Transcriptional Response of Candida albicans upon Internalization by Macrophages
M. Lorenz (2004)
10.1016/j.cub.2012.05.043
Candida albicans
J. Berman (2012)
ProtTest 3: fast selection
D. 1171 Darriba (2011)
10.1038/NPRE.2012.6837.2
Detecting differential usage of exons from RNA-Seq data
S. Anders (2012)
10.1146/annurev-phyto-072910-095355
Reactive oxygen species in phytopathogenic fungi: signaling, development, and disease.
J. Heller (2011)
10.1016/j.tim.2014.07.001
Metabolism impacts upon Candida immunogenicity and pathogenicity at multiple levels
A. Brown (2014)
10.1038/nbt.1508
Design and analysis of ChIP-seq experiments for DNA-binding proteins
P. Kharchenko (2008)
10.7554/eLife.00662
The evolution of drug resistance in clinical isolates of Candida albicans
Christopher B. Ford (2015)
10.1073/pnas.0911905107
Gene duplication and the evolution of ribosomal protein gene regulation in yeast
Ilan Wapinski (2010)
Practical Guidelines
K. Abdallah (2016)
10.1093/bioinformatics/btr088
ProtTest 3: fast selection of best-fit models of protein evolution
Diego Darriba (2011)
10.1091/MBC.12.10.2987
Genomic expression responses to DNA-damaging agents and the regulatory role of the yeast ATR homolog Mec1p.
A. Gasch (2001)
10.1093/molbev/mst042
Comparative Genome Analysis and Gene Finding in Candida Species Using CGOB
S. Maguire (2013)
Bio fi lm matrix regulation by Candida albicans Zap 1
E. P. Fox (2009)
10.1128/IAI.71.9.5344-5354.2003
Calcineurin Is Essential for Virulence in Candida albicans
Teresa Bader (2003)
10.1146/ANNUREV.MICRO.56.012302.160907
Evolution of drug resistance in Candida albicans.
L. Cowen (2002)
10.1038/nprot.2012.016
Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks
C. Trapnell (2012)
10.1128/AEM.07486-11
Caenorhabditis elegans, a Model Organism for Investigating Immunity
E. Marsh (2012)
10.1128/AAC.01343-10
Regulation of Efflux Pump Expression and Drug Resistance by the Transcription Factors Mrr1, Upc2, and Cap1 in Candida albicans †
S. Schubert (2011)
10.1016/J.ETP.2005.05.008
Metabolism and bioactivation of toxicants in the lung. The in vitro cellular approach.
J. Castell (2005)
10.1046/J.1523-1747.1999.00525.X
In vivo expression and localization of Candida albicans secreted aspartyl proteinases during oral candidiasis in HIV-infected patients.
M. Schaller (1999)
10.1128/IAI.00627-09
Ce-Duox1/BLI-3 Generates Reactive Oxygen Species as a Protective Innate Immune Mechanism in Caenorhabditis elegans
V. Chávez (2009)
Innate vs . adaptive immunity in Candida albicans infection
B. Bodendorfer (2003)
Fast and accurate short read alignment with Burrows
H. Li (2009)
10.1111/j.1462-5822.2007.00898.x
Differential susceptibility of mitogen‐activated protein kinase pathway mutants to oxidative‐mediated killing by phagocytes in the fungal pathogen Candida albicans
D. Arana (2007)
10.1002/eji.200636532
NADPH oxidase of human dendritic cells: Role in Candida albicans killing and regulation by interferons, dectin‐1 and CD206
M. Donini (2007)
10.1093/nar/gkr945
The Candida genome database incorporates multiple Candida species: multispecies search and analysis tools with curated gene and protein information for Candida albicans and Candida glabrata
Diane O. Inglis (2012)
10.1093/bioinformatics/btl446
RAxML-VI-HPC: maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models
A. Stamatakis (2006)
In vivo systematic analysis
P. 1388 Vandeputte (2011)
10.1016/J.FREERADBIOMED.2005.11.019
Cap1p is involved in multiple pathways of oxidative stress response in Candida albicans.
Y. Wang (2006)
Caenorhabditis elegans, a model organism
E. K. Marsh (2012)
10.7554/eLife.00603
Evolutionary principles of modular gene regulation in yeasts
D. Thompson (2013)
10.1046/j.1365-2958.1999.01590.x
Secreted aspartic proteinase (Sap) activity contributes to tissue damage in a model of human oral candidosis
M. Schaller (1999)
10.1128/MCB.11.5.2723
Association of RAP1 binding sites with stringent control of ribosomal protein gene transcription in Saccharomyces cerevisiae.
C. M. Moehle (1991)
10.1371/journal.pbio.1000133
Biofilm Matrix Regulation by Candida albicans Zap1
C. J. Nobile (2009)
10.1016/j.stem.2010.07.016
Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators.
Nicola K. Wilson (2010)
10.1128/EC.00290-12
Candida albicans Induces Arginine Biosynthetic Genes in Response to Host-Derived Reactive Oxygen Species
C. Jiménez-López (2012)
10.1128/EC.00367-08
A Pathogenesis Assay Using Saccharomycescerevisiae and Caenorhabditiselegans Reveals Novel Roles for Yeast AP-1, Yap1, and Host Dual Oxidase BLI-3 in Fungal Pathogenesis
C. Jain (2009)
10.1128/IAI.66.5.1953-1961.1998
Cloning and Sequencing of a Candida albicans Catalase Gene and Effects of Disruption of This Gene
D. R. Wysong (1998)
10.1093/bioinformatics/btq033
BEDTools: a flexible suite of utilities for comparing genomic features
Aaron R. Quinlan (2010)
Innate vs. adaptive immunity in Candida albicans infection
R B Ashman (2004)
10.1093/nar/gkt997
JASPAR 2014: an extensively expanded and updated open-access database of transcription factor binding profiles
A. Mathelier (2014)
10.1093/MOLBEV/MSM088
PAML 4: phylogenetic analysis by maximum likelihood.
Z. Yang (2007)
10.1006/JMBI.2000.3519
Computational identification of cis-regulatory elements associated with groups of functionally related genes in Saccharomyces cerevisiae.
J. D. Hughes (2000)
10.1371/journal.pcbi.1000279
Precise Regulation of Gene Expression Dynamics Favors Complex Promoter Architectures
D. Müller (2009)
10.1186/1471-2164-13-396
RNA sequencing revealed novel actors of the acquisition of drug resistance in Candida albicans
Sanjiveeni Dhamgaye (2012)
10.1002/CFG.V6:7/8
In silico analysis for transcription factors with Zn(II) 2 C 6 binuclear cluster DNA-binding domains in Candida albicans: Research Articles
S. Maicas (2005)
10.1111/mmi.12327
Analysis of a fungus‐specific transcription factor family, the Candida albicans zinc cluster proteins, by artificial activation
R. Schillig (2013)
Candida albicans Sfl1 suppresses flocculation
J. Bauer (2007)
10.1007/s00294-003-0381-8
Transcriptional control of nonfermentative metabolism in the yeast Saccharomyces cerevisiae
H. Schüller (2003)
Life and death in a macrophage: role
M. C. 1267 Lorenz (2002)
Candida albicans S fl 1 suppresses fl occulation and fi lamentation
L. Bohm (2016)
10.1038/nature04588
An excitable gene regulatory circuit induces transient cellular differentiation
Gürol M. Süel (2006)
10.1126/SCIENCE.291.5505.878
Bakers' yeast, a model for fungal biofilm formation.
T. Reynolds (2001)
10.1038/355601A0
Crisscross regulation of cell-type-specific gene expression during development in B. subtilis
R. Losick (1992)
10.1007/978-1-4419-8059-5_6
Innate immunity in C. elegans.
I. Engelmann (2010)
Candida albicans is phagocytosed, killed
S. L. Newman (2001)
10.1091/MBC.E05-06-0501
Role of the Hog1 stress-activated protein kinase in the global transcriptional response to stress in the fungal pathogen Candida albicans.
B. Enjalbert (2006)
10.1016/S1369-5274(01)00275-2
Transcriptional control of dimorphism in Candida albicans.
H. Liu (2001)
10.1111/j.1600-0854.2009.00877.x
Intraphagosomal measurement of the magnitude and duration of the oxidative burst.
B. VanderVen (2009)
10.1128/EC.00163-09
Candida albicans Hyphal Formation and Virulence Assessed Using a Caenorhabditis elegans Infection Model
R. Pukkila-Worley (2009)
10.1101/gad.1781909
Dynamic and complex transcription factor binding during an inducible response in yeast.
L. Ni (2009)
10.1128/IAI.69.11.6813-6822.2001
Candida albicans Is Phagocytosed, Killed, and Processed for Antigen Presentation by Human Dendritic Cells
S. Newman (2001)
10.1385/IR:26:1-3:095
Macrophage signaling and respiratory burst
K. Iles (2002)
10.1111/j.1365-2958.2008.06528.x
Candida albicans cell surface superoxide dismutases degrade host-derived reactive oxygen species to escape innate immune surveillance
Ingrid E Frohner (2009)
10.1093/bioinformatics/btp616
edgeR: a Bioconductor package for differential expression analysis of digital gene expression data
M. Robinson (2010)
10.1111/j.1365-2958.2004.04214.x
Regulatory networks affected by iron availability in Candida albicans
C. Lan (2004)
10.1038/nature08064
Evolution of pathogenicity and sexual reproduction in eight Candida genomes
G. Butler (2009)
Mutations in alternative carbon utilization
M. A. 1333 Ramirez (2007)
10.1534/GENETICS.104.032656
Genetic and Biochemical Interactions Among Yar1, Ltv1 and RpS3 Define Novel Links Between Environmental Stress and Ribosome Biogenesis in Saccharomyces cerevisiae
Jesse W Loar (2004)
10.1016/S1369-5274(98)80116-1
Dimorphism and virulence in Candida albicans.
A. Mitchell (1998)
10.1093/bioinformatics/btr189
MEME-ChIP: motif analysis of large DNA datasets
P. Machanick (2011)
10.1093/bioinformatics/bts196
RNA-SeQC: RNA-seq metrics for quality control and process optimization
D. DeLuca (2012)
PAL2NAL: robust conversion of protein
M. Suyama (2006)
10.1093/bioinformatics/btp348
trimAl: a tool for automated alignment trimming in large-scale phylogenetic analyses
S. Capella-Gutiérrez (2009)
10.1016/j.bbrc.2014.03.059
The type II Ca2+/calmodulin-dependent protein kinases are involved in the regulation of cell wall integrity and oxidative stress response in Candida albicans.
X. Ding (2014)
10.1186/gb-2008-9-9-r137
Model-based Analysis of ChIP-Seq (MACS)
Y. Zhang (2008)
10.1128/IAI.00102-07
Candida albicans Iff11, a Secreted Protein Required for Cell Wall Structure and Virulence
S. Bates (2007)
10.1371/journal.pgen.1001070
The Transcriptomes of Two Heritable Cell Types Illuminate the Circuit Governing Their Differentiation
Brian B. Tuch (2010)
10.1016/J.BBAMCR.2007.08.008
Disruption of aldo-keto reductase genes leads to elevated markers of oxidative stress and inositol auxotrophy in Saccharomyces cerevisiae.
Q. Chang (2008)
10.1128/EC.00372-06
Mutations in Alternative Carbon Utilization Pathways in Candida albicans Attenuate Virulence and Confer Pleiotropic Phenotypes
M. Ramírez (2006)
10.1046/j.0818-9641.2004.01217.x
Innate versus adaptive immunity in Candida albicans infection
R. Ashman (2004)
Differential gene
C. 1382 Trapnell (2012)
10.1186/1471-2105-12-323
RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome
Bo Li (2011)
10.1091/MBC.11.12.4241
Genomic expression programs in the response of yeast cells to environmental changes.
A. Gasch (2000)
10.1371/journal.ppat.1000227
Dynamic, Morphotype-Specific Candida albicans β-Glucan Exposure during Infection and Drug Treatment
Robert T Wheeler (2008)
10.1038/nbt.1754
Integrative Genomics Viewer
J. Robinson (2011)
10.1128/JB.182.2.320-326.2000
Isolation of the MIG1 gene from Candida albicans and effects of its disruption on catabolite repression.
Ó. Zaragoza (2000)
Analysis of a fungus - speci fi c transcription factor family , the Candida albicans zinc cluster proteins , by arti fi cial activation
S. Znaidi (2013)
10.1371/journal.pone.0026962
In Vivo Systematic Analysis of Candida albicans Zn2-Cys6 Transcription Factors Mutants for Mice Organ Colonization
P. Vandeputte (2011)
10.1016/S0968-0004(99)01460-7
The economics of ribosome biosynthesis in yeast.
J. Warner (1999)
10.1111/j.1462-5822.2012.01813.x
Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen
Iuliana V. Ene (2012)
10.1101/GAD.1389306
Target hub proteins serve as master regulators of development in yeast.
Anthony R. Borneman (2006)
Evolution of drug resistance
L. E. Cowen (2002)
Reactive oxygen species in phytopathogenic fungi
J. Heller (2011)
10.1128/EC.1.5.657-662.2002
Life and Death in a Macrophage: Role of the Glyoxylate Cycle in Virulence
M. Lorenz (2002)
10.1016/j.cell.2011.01.032
Control of the Embryonic Stem Cell State
R. Young (2011)
10.1093/nar/gkl315
PAL2NAL: robust conversion of protein sequence alignments into the corresponding codon alignments
M. Suyama (2006)
10.1038/msb4100018
Extension of a genetic network model by iterative experimentation and mathematical analysis
J. Locke (2005)
10.1038/ng.605
Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity
S. Noble (2010)
Detecting differential usage of exons
S. 1125 Anders (2012)
10.1371/journal.pgen.1000783
A Phenotypic Profile of the Candida albicans Regulatory Network
Oliver R. Homann (2009)
10.1371/journal.pone.0017046
From Attachment to Damage: Defined Genes of Candida albicans Mediate Adhesion, Invasion and Damage during Interaction with Oral Epithelial Cells
B. Waechtler (2011)



This paper is referenced by
10.1534/genetics.116.199679
Adaptation of Candida albicans to Reactive Sulfur Species
Yasmin Chebaro (2017)
Candida albicans infected macrophages 2 3
J F Muñoz (2019)
10.1186/s13568-018-0647-7
Identification of genome-wide binding sites of heat shock factor 1, Hsf1, under basal conditions in the human pathogenic yeast, Candida albicans
R. Nair (2018)
10.1038/s41467-019-09599-8
Coordinated host-pathogen transcriptional dynamics revealed using sorted subpopulations and single macrophages infected with Candida albicans
J. F. Muñoz (2019)
10.1038/s41467-018-04787-4
Gene flow contributes to diversification of the major fungal pathogen Candida albicans
Jeanne Ropars (2018)
10.1007/s00430-019-00635-4
Caenorhabditis elegans as a model animal for investigating fungal pathogenesis
M. Madende (2019)
10.1016/j.micpath.2018.02.028
Candida albicans - Biology, molecular characterization, pathogenicity, and advances in diagnosis and control - An update.
Maryam Dadar (2018)
10.3389/fmicb.2017.02555
The Mitochondrial GTPase Gem1 Contributes to the Cell Wall Stress Response and Invasive Growth of Candida albicans
B. Koch (2017)
10.3389/fmicb.2019.02945
The Fungal-Specific Transcription Factor VpFSTF1 Is Required for Virulence in Valsa pyri
A. Kange (2019)
10.1101/350322
Coordinated host-pathogen transcriptional dynamics revealed using sorted subpopulations and single, Candida albicans infected macrophages
J. F. Muñoz (2018)
The Zinc cluster transcription factor ZtfA is an activator of asexual development and secondary metabolism and regulates the oxidative stress response in the filamentous fungus Aspergillus nidulans
Karl G. Thieme (2018)
10.1534/g3.120.401340
Transcriptome Analyses of Candida albicans Biofilms, Exposed to Arachidonic Acid and Fluconazole, Indicates Potential Drug Targets
O. Kuloyo (2020)
10.1093/femsyr/foy078
Two negative regulators of biofilm development exhibit functional divergence in conferring virulence potential to Candida albicans
P. Kakade (2019)
10.1534/g3.119.400777
rmtA-Dependent Transcriptome and Its Role in Secondary Metabolism, Environmental Stress, and Virulence in Aspergillus flavus
Timothy Satterlee (2019)
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