Skip to main content

14 Integration of Metabolism with Virulence in Candida albicans

  • 2014 Accesses

Part of the The Mycota book series (MYCOTA,volume 13)

Abstract

The genome of the model pathogenic fungus Candida albicans was sequenced about a decade ago, facilitating unbiased genome-wide explorations of its pathobiology. These studies, in combination with the molecular and biochemical dissection of specific pathways and networks, have revealed that metabolic adaptation is intimately linked with the virulence of C. albicans. This fungus tunes its metabolic activity to specific host niches, and its virulence depends on the functionality of certain metabolic pathways. Also, its pathogenicity and antifungal drug susceptibility are modulated by growth on nutrients found in such niches. Specific regulators appear to coordinate the expression of metabolic functions with virulence factors such as yeast-hypha morphogenesis, thereby promoting host colonisation. It has become clear that the regulatory networks controlling certain metabolic pathways in C. albicans have undergone transcriptional rewiring in comparison with Saccharomyces cerevisiae, reflecting the evolutionary tuning of C. albicans to mammalian host niches.

Keywords

  • Amino Acid Metabolism
  • Glyoxylate Cycle
  • Central Carbon Metabolism
  • Phenotypic Switching
  • Amino Acid Starvation

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

This is a preview of subscription content, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-642-45218-5_14
  • Chapter length: 22 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   169.00
Price excludes VAT (USA)
  • ISBN: 978-3-642-45218-5
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   219.99
Price excludes VAT (USA)
Hardcover Book
USD   279.99
Price excludes VAT (USA)
Fig. 14.1.
Fig. 14.2.
Fig. 14.3.

Abbreviations

3AT:

3-aminotriazole

bHLH:

β-helix loop helix domain

GCN response:

General amino acid control

ROS:

Reactive oxygen species

GCRE:

GCN Response Element

uORF:

upstream Open Reading Frame

References

  • Albrecht G, Mosch HU, Hoffmann B, Reusser U, Braus GH (1998) Monitoring the Gcn4 protein-mediated response in the yeast Saccharomyces cerevisiae. J Biol Chem 273:12696–12702

    PubMed  CAS  Google Scholar 

  • Almeida RS, Wilson D, Hube B (2009) Candida albicans iron acquisition within the host. FEMS Yeast Res 9:1000–1012

    PubMed  CAS  Google Scholar 

  • Alonso-Monge R, Navarro-García F, Molero G, Diez-Orejas R, Gustin M, Pla J, Sánchez M, Nombela C (1999) Role of the mitogen-activated protein kinase Hog1p in morphogenesis and virulence of Candida albicans. J Bacteriol 181:3058–3068

    PubMed Central  PubMed  CAS  Google Scholar 

  • Andes D, Lepak A, Pitula A, Marchillo K, Clark J (2005) A simple approach for estimating gene expression in Candida albicans directly from a systemic infection site. J Infect Dis 192:893–900

    PubMed  CAS  Google Scholar 

  • Askew C, Sellam A, Epp E, Hogues H, Mullick A, Nantel A, Whiteway M (2009) Transcriptional regulation of carbohydrate metabolism in the human pathogen Candida albicans. PLoS Pathog 5:e1000612

    PubMed Central  PubMed  Google Scholar 

  • Bailey DA, Feldmann PJ, Bovey M, Gow NA, Brown AJ (1996) The Candida albicans HYR1 gene, which is activated in response to hyphal development, belongs to a gene family encoding yeast cell wall proteins. J Bacteriol 178:5353–5360

    PubMed Central  PubMed  CAS  Google Scholar 

  • Barelle CJ, Manson CL, MacCallum DM, Odds FC, Gow NA, Brown AJ (2004) GFP as a quantitative reporter of gene regulation in Candida albicans. Yeast 21:333–340

    PubMed  CAS  Google Scholar 

  • Barelle CJ, Priest CL, Maccallum DM, Gow NA, Odds FC, Brown AJ (2006) Niche-specific regulation of central metabolic pathways in a fungal pathogen. Cell Microbiol 8:961–971

    PubMed Central  PubMed  CAS  Google Scholar 

  • Bertram G, Swoboda RK, Gooday GW, Gow NA, Brown AJ (1996) Structure and regulation of the Candida albicans ADH1 gene encoding an immunogenic alcohol dehydrogenase. Yeast 12:115–127

    PubMed  CAS  Google Scholar 

  • Biswas K, Morschhauser J (2005) The Mep2p ammonium permease controls nitrogen starvation-induced filamentous growth in Candida albicans. Mol Microbiol 56:649–669

    PubMed  CAS  Google Scholar 

  • Blankenship JR, Mitchell AP (2006) How to build a biofilm: a fungal perspective. Curr Opin Microbiol 9:588–594

    PubMed  CAS  Google Scholar 

  • Bockmuhl DP, Ernst JF (2001) A potential phosphorylation site for an A-type kinase in the Efg1 regulator protein contributes to hyphal morphogenesis of Candida albicans. Genetics 157:1523–1530

    PubMed Central  PubMed  CAS  Google Scholar 

  • Boeckstaens M, Andre B, Marini AM (2007) The yeast ammonium transport protein Mep2 and its positive regulator, the Npr1 kinase, play an important role in normal and pseudohyphal growth on various nitrogen media through retrieval of excreted ammonium. Mol Microbiol 64:534–546

    PubMed  CAS  Google Scholar 

  • Brand A (2012) Hyphal growth in human fungal pathogens and its role in virulence. Int J Microbiol 2012:517529

    PubMed Central  PubMed  Google Scholar 

  • Brand A, MacCallum DM, Brown AJ, Gow NA, Odds FC (2004) Ectopic expression of URA3 can influence the virulence phenotypes and proteome of Candida albicans but can be overcome by targeted reintegration of URA3 at the RPS10 locus. Eukaryot Cell 3:900–909

    PubMed Central  PubMed  CAS  Google Scholar 

  • Braun BR, Johnson AD (1997) Control of filament formation in Candida albicans by the transcriptional repressor TUP1. Science 277:105–109

    PubMed  CAS  Google Scholar 

  • Braun BR, Kadosh D, Johnson AD (2001) NRG1, a repressor of filamentous growth in C. albicans, is down-regulated during filament induction. EMBO J 20:4753–4761

    PubMed Central  PubMed  CAS  Google Scholar 

  • Brega E, Zufferey R, Mamoun CB (2004) Candida albicans Csy1p is a nutrient sensor important for activation of amino acid uptake and hyphal morphogenesis. Eukaryot Cell 3:135–143

    PubMed Central  PubMed  CAS  Google Scholar 

  • Brock M (2009) Fungal metabolism in host niches. Curr Opin Microbiol 12:371–376

    PubMed  CAS  Google Scholar 

  • Brown AJ (2005) Integration of metabolism with virulence in Candida albicans. In: Brown AJ (ed) The Mycota, vol 13, Fungal genomics. Springer, Berlin, pp 185–203

    Google Scholar 

  • Brown AJ, Gow NA (1999) Regulatory networks controlling Candida albicans morphogenesis. Trends Microbiol 7:333–338

    PubMed  CAS  Google Scholar 

  • Brown AJ, Barelle CJ, Budge S, Duncan J, Harris S, Lee PR, Leng P, Macaskill S, Abdul Murad AM, Ramsdale M, Wiltshire C, Wishart JA, Gow NA (2000) Gene regulation during morphogenesis in Candida albicans. Contrib Microbiol 5:112–125

    PubMed  CAS  Google Scholar 

  • Brown AJ, Odds FC, Gow NA (2007) Infection-related gene expression in Candida albicans. Curr Opin Microbiol 10:307–313

    PubMed  CAS  Google Scholar 

  • Brown V, Sabina J, Johnston M (2009) Specialized sugar sensing in diverse fungi. Curr Biol 19:436–441

    PubMed Central  PubMed  CAS  Google Scholar 

  • Brown AJ, Haynes K, Gow NAR, Quinn J (2011) Stress responses in Candida. In: Clancy CJ, Calderone RA (eds) Candida and candidiasis, 2nd edn. ASM Press, Washington, DC, pp 225–242

    Google Scholar 

  • Bruneau JM, Maillet I, Tagat E, Legrand R, Supatto F, Fudali C, Caer JP, Labas V, Lecaque D, Hodgson J (2003) Drug induced proteome changes in Candida albicans: comparison of the effect of beta(1,3) glucan synthase inhibitors and two triazoles, fluconazole and itraconazole. Proteomics 3:325–336

    PubMed  CAS  Google Scholar 

  • Calderone R (2002) Candida and candidiasis. ASM Press, Washington, DC

    Google Scholar 

  • Calderone RA, Clancy CJ (2011) Candida and candidiasis. ASM Press, Washington, DC

    Google Scholar 

  • Chauvel M, Nesseir A, Cabral V, Znaidi S, Goyard S, Bachellier-Bassi S, Firon A, Legrand M, Diogo D, Naulleau C, Rossignol T, d’Enfert C (2012) A versatile overexpression strategy in the pathogenic yeast Candida albicans: identification of regulators of morphogenesis and fitness. PLoS One 7:e45912

    PubMed Central  PubMed  CAS  Google Scholar 

  • Citiulo F, Jacobsen ID, Miramón P, Schild L, Brunke S, Zipfel P, Brock M, Hube B, Wilson D (2012) Candida albicans scavenges host zinc via Pra1 during endothelial invasion. PLoS Pathog 8:e1002777

    PubMed Central  PubMed  CAS  Google Scholar 

  • Cowen LE, Nantel A, Whiteway MS, Thomas DY, Tessier DC, Kohn LM, Anderson JB (2002) Population genomics of drug resistance in Candida albicans. Proc Natl Acad Sci U S A 99:9284–9289

    PubMed Central  PubMed  CAS  Google Scholar 

  • De Backer MD, Nelissen B, Logghe M, Viaene J, Loonen I, Vandoninck S, de Hoogt R, Dewaele S, Simons FA, Verhasselt P, Vanhoof G, Contreras R, Luyten WH (2001) An antisense-based functional genomics approach for identification of genes critical for growth of Candida albicans. Nat Biotechnol 19:235–241

    PubMed  Google Scholar 

  • Dever TE, Feng L, Wek RC, Cigan AM, Donahue TF, Hinnebusch AG (1992) Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Cell 68:585–596

    PubMed  CAS  Google Scholar 

  • Doedt T, Krishnamurthy S, Bockmühl DP, Tebarth B, Stempel C, Russell CL, Brown AJ, Ernst JF (2004) APSES proteins regulate morphogenesis and metabolism in Candida albicans. Mol Biol Cell 15:3167–3180

    PubMed Central  PubMed  CAS  Google Scholar 

  • Ellenberger TE, Brandl CJ, Struhl K, Harrison SC (1992) The GCN4 basic region leucine zipper binds DNA as a dimer of uninterrupted alpha helices: crystal structure of the protein-DNA complex. Cell 71:1223–1237

    PubMed  CAS  Google Scholar 

  • Ene IV, Adya AK, Wehmeier S, Brand AC, MacCallum DM, Gow NA, Brown AJ (2012a) Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen. Cell Microbiol 14:1319–1335

    PubMed Central  PubMed  CAS  Google Scholar 

  • Ene IV, Heilmann CJ, Sorgo AG, Walker LA, de Koster CG, Munro CA, Klis FM, Brown AJ (2012b) Carbon source-induced reprogramming of the cell wall proteome and secretome modulates the adherence and drug resistance of the fungal pathogen Candida albicans. Proteomics 12:3164–3179

    PubMed Central  PubMed  CAS  Google Scholar 

  • Ene IV, Cheng SC, Netea MG, Brown AJ (2013) Growth of Candida albicans cells on the physiologically relevant carbon source lactate affects their recognition and phagocytosis by immune cells. Infect Immun 81:238–248

    PubMed Central  PubMed  CAS  Google Scholar 

  • Enjalbert B, Nantel A, Whiteway M (2003) Stress-induced gene expression in Candida albicans: absence of a general stress response. Mol Biol Cell 14:1460–1467

    PubMed Central  PubMed  CAS  Google Scholar 

  • Enjalbert B, MacCallum DM, Odds FC, Brown AJ (2007) Niche-specific activation of the oxidative stress response by the pathogenic fungus Candida albicans. Infect Immun 75:2143–2151

    PubMed Central  PubMed  CAS  Google Scholar 

  • Fradin C, Kretschmar M, Nichterlein T, Gaillardin C, d’Enfert C, Hube B (2003) Stage-specific gene expression of Candida albicans in human blood. Mol Microbiol 47:1523–1543

    PubMed  CAS  Google Scholar 

  • Fradin C, De Groot P, MacCallum D, Schaller M, Klis F, Odds FC, Hube B (2005) Granulocytes govern the transcriptional response, morphology and proliferation of Candida albicans in human blood. Mol Microbiol 56:397–415

    PubMed  CAS  Google Scholar 

  • Gancedo JM (1998) Yeast carbon catabolite repression. Microbiol Mol Biol Rev 62:334–361

    PubMed Central  PubMed  CAS  Google Scholar 

  • Garcia-Sanchez S, Aubert S, Iraqui I, Janbon G, Ghigo JM, d’Enfert C (2004) Candida albicans biofilms: a developmental state associated with specific and stable gene expression patterns. Eukaryot Cell 3:536–545

    PubMed Central  PubMed  CAS  Google Scholar 

  • García-Sánchez S, Mavor AL, Russell CL, Argimon S, Dennison P, Enjalbert B, Brown AJ (2005) Global roles of Ssn6 in Tup1- and Nrg1-dependent gene regulation in the fungal pathogen, Candida albicans. Mol Biol Cell 16:2913–2925

    PubMed Central  PubMed  Google Scholar 

  • Gow NA, Knox Y, Munro CA, Thompson WD (2003) Infection of chick chorioallantoic membrane (CAM) as a model for invasive hyphal growth and pathogenesis of Candida albicans. Med Mycol 41:331–338

    PubMed  CAS  Google Scholar 

  • Gow NA, van de Veerdonk FL, Brown AJ, Netea MG (2011) Candida albicans morphogenesis and host defence: discriminating invasion from colonization. Nat Rev Microbiol 10:112–122

    PubMed Central  PubMed  Google Scholar 

  • Harris AD, Castro J, Sheppard DC, Carmeli Y, Samore MH (1999) Risk factors for nosocomial candiduria due to Candida glabrata and Candida albicans. Clin Infect Dis 29:926–928

    PubMed  CAS  Google Scholar 

  • Hellstein J, Vawter-Hugart H, Fotos P, Schmid J, Soll DR (1993) Genetic similarity and phenotypic diversity of commensal and pathogenic strains of Candida albicans isolated from the oral cavity. J Clin Microbiol 31:3190–3199

    PubMed Central  PubMed  CAS  Google Scholar 

  • Hinnebusch AG (1988) Mechanisms of gene regulation in the general control of amino acid biosynthesis in Saccharomyces cerevisiae. Microbiol Rev 52:248–273

    PubMed Central  PubMed  CAS  Google Scholar 

  • Hinnebusch AG, Natarajan K (2002) Gcn4p, a master regulator of gene expression, is controlled at multiple levels by diverse signals of starvation and stress. Eukaryot Cell 1:22–32

    PubMed Central  PubMed  CAS  Google Scholar 

  • Hoffmann B, Valerius O, Andermann M, Braus GH (2001) Transcriptional autoregulation and inhibition of mRNA translation of amino acid regulator gene cpcA of filamentous fungus Aspergillus nidulans. Mol Biol Cell 12:2846–2857

    PubMed Central  PubMed  CAS  Google Scholar 

  • Hoyer LL, Green CB, Oh SH, Zhao X (2008) Discovering the secrets of the Candida albicans agglutinin-like sequence (ALS) gene family – a sticky pursuit. Med Mycol 46:1–15

    PubMed Central  PubMed  CAS  Google Scholar 

  • Huang G (2012) Regulation of phenotypic transitions in the fungal pathogen Candida albicans. Virulence 3:251–261

    PubMed Central  PubMed  Google Scholar 

  • Hudson DA, Sciascia QL, Sanders RJ, Norris GE, Edwards PJB, Sullivan PA, Farley PC (2004) Identification of the dialysable serum inducer of germ-tube formation in Candida albicans. Microbiology 150:3041–3049

    PubMed  CAS  Google Scholar 

  • Ihmels J, Bergmann S, Gerami-Nejad M, Yanai I, McClellan M, Berman J, Barkai N (2005) Rewiring of the yeast transcriptional network through the evolution of motif usage. Science 309:938–940

    PubMed  CAS  Google Scholar 

  • Jiménez-López C, Collette JR, Brothers KM, Shepardson KM, Cramer RA, Wheeler RT, Lorenz MC (2013) Candida albicans induces arginine biosynthetic genes in response to host-derived reactive oxygen species. Eukaryot Cell 12:91–100

    PubMed Central  PubMed  Google Scholar 

  • Johnston M (1999) Feasting, fasting and fermenting. Glucose sensing in yeast and other cells. Trends Genet 15:29–33

    PubMed  CAS  Google Scholar 

  • Jones T, Federspiel NA, Chibana H, Dungan J, Kalman S, Magee BB, Newport G, Thorstenson YR, Agabian N, Magee PT, Davis RW, Scherer S (2004) The diploid genome sequence of Candida albicans. Proc Natl Acad Sci U S A 101:7329–7334

    PubMed Central  PubMed  CAS  Google Scholar 

  • Kadosh D, Johnson AD (2001) Rfg1, a protein related to the Saccharomyces cerevisiae hypoxic regulator Rox1, controls filamentous growth and virulence in Candida albicans. Mol Cell Biol 21:2496–2505

    PubMed Central  PubMed  CAS  Google Scholar 

  • Kadosh D, Johnson AD (2005) Induction of the Candida albicans filamentous growth program by relief of transcriptional repression: a genome-wide analysis. Mol Biol Cell 16:2903–2912

    PubMed Central  PubMed  CAS  Google Scholar 

  • Kastaniotis AJ, Zitomer RS (2000) Rox1 mediated repression. Oxygen dependent repression in yeast. Adv Exp Med Biol 475:185–195

    PubMed  CAS  Google Scholar 

  • Khalaf RA, Zitomer RS (2001) The DNA binding protein Rfg1 is a repressor of filamentation in Candida albicans. Genetics 157:1503–1512

    PubMed Central  PubMed  CAS  Google Scholar 

  • Kim J, Sudbery P (2011) Candida albicans, a major human fungal pathogen. J Microbiol 49:171–177

    PubMed  Google Scholar 

  • Klis FM, Sosinska GJ, de Groot PW, Brul S (2009) Covalently linked cell wall proteins of Candida albicans and their role in fitness and virulence. FEMS Yeast Res 9:1013–1028

    PubMed  CAS  Google Scholar 

  • Koh AY, Kohler JR, Coggshall KT, Van Rooijen N, Pier GB (2008) Mucosal damage and neutropenia are required for Candida albicans dissemination. PLoS Pathog 4:e35

    PubMed Central  PubMed  Google Scholar 

  • Kornitzer D, Raboy B, Kulka RG, Fink GR (1994) Regulated degradation of the transcription factor Gcn4. EMBO J 13:6021–6030

    PubMed Central  PubMed  CAS  Google Scholar 

  • Korting HC, Hube B, Oberbauer S, Januschke E, Hamm G, Albrecht A, Borelli C, Schaller M (2003) Reduced expression of the hyphal-independent Candida albicans proteinase genes SAP1 and SAP3 in the efg1 mutant is associated with attenuated virulence during infection of oral epithelium. J Med Microbiol 52:623–632

    PubMed  CAS  Google Scholar 

  • Krishnamoorthy T, Pavitt GD, Zhang F, Dever TE, Hinnebusch AG (2001) Tight binding of the phosphorylated alpha subunit of initiation factor 2 (eIF2alpha) to the regulatory subunits of guanine nucleotide exchange factor eIF2B is required for inhibition of translation initiation. Mol Cell Biol 21:5018–5030

    PubMed Central  PubMed  CAS  Google Scholar 

  • Lachke SA, Lockhart SR, Daniels KJ, Soll DR (2003) Skin facilitates Candida albicans mating. Infect Immun 71:4970–4976

    PubMed Central  PubMed  CAS  Google Scholar 

  • Lan CY, Newport G, Murillo LA, Jones T, Scherer S, Davis RW, Agabian N (2002) Metabolic specialization associated with phenotypic switching in Candida albicans. Proc Natl Acad Sci U S A 99:14907–14912

    PubMed Central  PubMed  CAS  Google Scholar 

  • Lane S, Birse C, Zhou S, Matson R, Liu H (2001) DNA array studies demonstrate convergent regulation of virulence factors by Cph1, Cph2, and Efg1 in Candida albicans. J Biol Chem 276:48988–48996

    PubMed  CAS  Google Scholar 

  • Lavoie H, Hogues H, Whiteway M (2009) Rearrangements of the transcriptional regulatory networks of metabolic pathways in fungi. Curr Opin Microbiol 12:655–663

    PubMed  CAS  Google Scholar 

  • Leach MD, Stead DA, Argo E, MacCallum DM, Brown AJP (2011) Proteomic and molecular analyses highlight the importance of ubiquitination for stress resistance, metabolic adaptation, morphogenetic regulation and virulence of Candida albicans. Mol Microbiol 79:1574–1593

    PubMed Central  PubMed  CAS  Google Scholar 

  • Leng P, Lee PR, Wu H, Brown AJ (2001) Efg1, a morphogenetic regulator in Candida albicans, is a sequence-specific DNA binding protein. J Bacteriol 183:4090–4093

    PubMed Central  PubMed  CAS  Google Scholar 

  • Lo HJ, Kohler JR, DiDomenico B, Loebenberg D, Cacciapuoti A, Fink GR (1997) Nonfilamentous C. albicans mutants are avirulent. Cell 90:939–949

    PubMed  CAS  Google Scholar 

  • Lohse MB, Johnson AD (2008) Differential phagocytosis of white versus opaque Candida albicans by Drosophila and mouse phagocytes. PLoS One 3:e1473

    PubMed Central  PubMed  Google Scholar 

  • Lohse MB, Johnson AD (2009) White-opaque switching in Candida albicans. Curr Opin Microbiol 12:650–654

    PubMed Central  PubMed  CAS  Google Scholar 

  • Lorenz MC, Fink GR (2001) The glyoxylate cycle is required for fungal virulence. Nature 412:83–86

    PubMed  CAS  Google Scholar 

  • Lorenz MC, Fink GR (2002) Life and death in a macrophage: role of the glyoxylate cycle in virulence. Eukaryot Cell 1:657–662

    PubMed Central  PubMed  CAS  Google Scholar 

  • Lorenz MC, Bender JA, Fink GR (2004) Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot Cell 3:1076–1087

    PubMed Central  PubMed  CAS  Google Scholar 

  • Maidan MM, Thevelein JM, Van Dijck P (2005) Carbon source induced yeast-to-hypha transition in Candida albicans is dependent on the presence of amino acids and on the G-protein-coupled receptor Gpr1. Biochem Soc Trans 33:291–293

    PubMed  CAS  Google Scholar 

  • Martchenko M, Alarco AM, Harcus D, Whiteway M (2004) Superoxide dismutases in Candida albicans: transcriptional regulation and functional characterization of the hyphal-induced SOD5 gene. Mol Biol Cell 15:456–467

    PubMed Central  PubMed  CAS  Google Scholar 

  • Martchenko M, Levitin A, Hogues H, Nantel A, Whiteway M (2007) Transcriptional rewiring of fungal galactose-metabolism circuitry. Curr Biol 17:1007–1013

    PubMed  CAS  Google Scholar 

  • Mayer FL, Wilson D, Jacobsen ID, Miramon P, Große K, Hube B (2012) The novel Candida albicans transporter Dur31 is a multi-stage pathogenicity factor. PLoS Pathog 8:e1002592

    PubMed Central  PubMed  CAS  Google Scholar 

  • Miramon P, Dunker C, Windecker H, Bohovych IM, Brown AJP, Kurzai O, Hube B (2012) Cellular responses of Candida albicans to phagocytosis and the extracellular activities of neutrophils are critical to counteract carbohydrate starvation, oxidative and nitrosative stress. PLoS One 7:e52850

    PubMed Central  PubMed  CAS  Google Scholar 

  • Mueller PP, Hinnebusch AG (1986) Multiple upstream AUG codons mediate translational control of GCN4. Cell 45:201–207

    PubMed  CAS  Google Scholar 

  • Murad AM, d’Enfert C, Gaillardin C, Tournu H, Tekaia F, Talibi D, Marechal D, Marchais V, Cottin J, Brown AJ (2001a) Transcript profiling in Candida albicans reveals new cellular functions for the transcriptional repressors CaTup1, CaMig1 and CaNrg1. Mol Microbiol 42:981–993

    PubMed  CAS  Google Scholar 

  • Murad AM, Leng P, Straffon M, Wishart J, Macaskill S, MacCallum D, Schnell N, Talibi D, Marechal D, Tekaia F, d’Enfert C, Gaillardin C, Odds FC, Brown AJ (2001b) NRG1 represses yeast-hypha morphogenesis and hypha-specific gene expression in Candida albicans. EMBO J 20:4742–4752

    PubMed Central  PubMed  CAS  Google Scholar 

  • Naglik J, Albrecht A, Bader O, Hube B (2004) Candida albicans proteinases and host/pathogen interactions. Cell Microbiol 6:915–926

    PubMed  CAS  Google Scholar 

  • Nailis H, Kucharíková S, Ricicová M, Van Dijck P, Deforce D, Nelis H, Coenye T (2010) Real-time PCR expression profiling of genes encoding potential virulence factors in Candida albicans biofilms: identification of model-dependent and -independent gene expression. BMC Microbiol 10:114

    PubMed Central  PubMed  Google Scholar 

  • Nantel A, Dignard D, Bachewich C, Harcus D, Marcil A, Bouin AP, Sensen CW, Hogues H, van het Hoog M, Gordon P, Rigby T, Benoit F, Tessier DC, Thomas DY, Whiteway M (2002) Transcription profiling of Candida albicans cells undergoing the yeast-to-hyphal transition. Mol Biol Cell 13:3452–3465

    PubMed Central  PubMed  CAS  Google Scholar 

  • Natarajan K, Meyer MR, Jackson BM, Slade D, Roberts C, Hinnebusch AG, Marton MJ (2001) Transcriptional profiling shows that Gcn4p is a master regulator of gene expression during amino acid starvation in yeast. Mol Cell Biol 21:4347–4368

    PubMed Central  PubMed  CAS  Google Scholar 

  • Navarro-Garcia F, Sanchez M, Nombela C, Pla J (2001) Virulence genes in the pathogenic yeast Candida albicans. FEMS Microbiol Rev 25:245–268

    PubMed  CAS  Google Scholar 

  • Nicholls S, Straffon M, Enjalbert B, Nantel A, Macaskill S, Whiteway M, Brown AJ (2004) Msn2- and Msn4-like transcription factors play no obvious roles in the stress responses of the fungal pathogen Candida albicans. Eukaryot Cell 3:1111–1123

    PubMed Central  PubMed  CAS  Google Scholar 

  • Niimi M, Kamiyama A, Tokunaga M (1988) Respiration of medically important Candida species and Saccharomyces cerevisiae in relation to glucose effect. J Med Vet Mycol 26:195–198

    PubMed  CAS  Google Scholar 

  • Nikolaou E, Agrafioti I, Stumpf M, Quinn J, Stansfield I, Brown AJP (2009) Phylogenetic diversity of stress signalling pathways in fungi. BMC Evol Biol 9:44

    PubMed Central  PubMed  Google Scholar 

  • Nobile CJ, Bruno VM, Richard ML, Davis DA, Mitchell AP (2003) Genetic control of chlamydospore formation in Candida albicans. Microbiology 149:3629–3637

    PubMed  CAS  Google Scholar 

  • Nobile CJ, Schneider HA, Nett JE, Sheppard DC, Filler SG, Andes DR, Mitchell AP (2008) Complementary adhesin function in C. albicans biofilm formation. Curr Biol 18:1017–1024

    PubMed Central  PubMed  CAS  Google Scholar 

  • Noble SM, French S, Kohn LA, Chen V, Johnson AD (2010) Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity. Nat Genet 42:590–598

    PubMed Central  PubMed  CAS  Google Scholar 

  • Odds FC (1988) Candida and candidosis. Bailliere Tindall, London

    Google Scholar 

  • Odds FC, Brown AJ, Gow NA (2003) Antifungal agents: mechanisms of action. Trends Microbiol 11:272–279

    PubMed  CAS  Google Scholar 

  • Oliphant AR, Brandl CJ, Struhl K (1989) Defining the sequence specificity of DNA-binding proteins by selecting binding sites from random-sequence oligonucleotides: analysis of yeast GCN4 protein. Mol Cell Biol 9:2944–2949

    PubMed Central  PubMed  CAS  Google Scholar 

  • Paluh JL, Orbach MJ, Legerton TL, Yanofsky C (1988) The cross-pathway control gene of Neurospora crassa, cpc-1, encodes a protein similar to GCN4 of yeast and the DNA-binding domain of the oncogene v-jun-encoded protein. Proc Natl Acad Sci U S A 85:3728–3732

    PubMed Central  PubMed  CAS  Google Scholar 

  • Perlroth J, Choi B, Spellberg B (2007) Nosocomial fungal infections: epidemiology, diagnosis, and treatment. Med Mycol 45:321–346

    PubMed  Google Scholar 

  • Petter R, Chang YC, Kwon-Chung KJ (1997) A gene homologous to Saccharomyces cerevisiae SNF1 appears to be essential for the viability of Candida albicans. Infect Immun 65:4909–4917

    PubMed Central  PubMed  CAS  Google Scholar 

  • Pfaller MA, Diekema DJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20:133–163

    PubMed Central  PubMed  CAS  Google Scholar 

  • Phan QT, Myers CL, Fu Y, Sheppard DC, Yeaman MR, Welch WH, Ibrahim AS, Edwards JE Jr, Filler SG (2007) Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells. PLoS Biol 5:e64

    PubMed Central  PubMed  Google Scholar 

  • Piekarska K, Mol E, van den Berg M, Hardy G, van den Burg J, van Roermund C, MacCallum D, Odds F, Distel B (2006) Peroxisomal fatty acid beta-oxidation is not essential for virulence of Candida albicans. Eukaryot Cell 5:1847–1856

    PubMed Central  PubMed  CAS  Google Scholar 

  • Pierce JV, Dignard D, Whiteway M, Kumamoto CA (2013) Normal adaptation of Candida albicans to the murine gastrointestinal tract requires Efg1p-dependent regulation of metabolic and host defense genes. Eukaryot Cell 12:37–49

    PubMed Central  PubMed  CAS  Google Scholar 

  • Ramirez MA, Lorenz MC (2007) Mutations in alternative carbon utilization pathways in Candida albicans attenuate virulence and confer pleiotropic phenotypes. Eukaryot Cell 6:280–290

    PubMed Central  PubMed  CAS  Google Scholar 

  • Rao GR, Ramakrishnan T, Sirsi M (1960) Enzymes in Candida albicans. I. Pathways of glucose dissimilation. J Bacteriol 80:654–658

    PubMed Central  PubMed  CAS  Google Scholar 

  • Rodaki A, Young T, Brown AJP (2006) Effects of depleting the essential central metabolic enzyme, fructose-1,6-bisphosphate aldolase, upon the growth and viability of Candida albicans: implications for antifungal drug target discovery. Eukaryot Cell 5:1371–1377

    PubMed Central  PubMed  CAS  Google Scholar 

  • Rodaki A, Bohovych IM, Enjalbert B, Young T, Odds FC, Gow NA, Brown AJ (2009) Glucose promotes stress resistance in the fungal pathogen Candida albicans. Mol Biol Cell 20:4845–4855

    PubMed Central  PubMed  CAS  Google Scholar 

  • Roemer T, Jiang B, Davison J, Ketela T, Veillette K, Breton A, Tandia F, Linteau A, Sillaots S, Marta C, Martel N, Veronneau S, Lemieux S, Kauffman S, Becker J, Storms R, Boone C, Bussey H (2003) Large-scale essential gene identification in Candida albicans and applications to antifungal drug discovery. Mol Microbiol 50:167–181

    PubMed  CAS  Google Scholar 

  • Rogers PD, Barker KS (2003) Genome-wide expression profile analysis reveals coordinately regulated genes associated with stepwise acquisition of azole resistance in Candida albicans clinical isolates. Antimicrob Agents Chemother 47:1220–1227

    PubMed Central  PubMed  CAS  Google Scholar 

  • Rolfes RJ, Hinnebusch AG (1993) Translation of the yeast transcriptional activator GCN4 is stimulated by purine limitation: implications for activation of the protein kinase GCN2. Mol Cell Biol 13:5099–5111

    PubMed Central  PubMed  CAS  Google Scholar 

  • Rolland F, Winderickx J, Thevelein JM (2001) Glucose-sensing mechanisms in eukaryotic cells. Trends Biochem Sci 26:310–317

    PubMed  CAS  Google Scholar 

  • Rubin-Bejerano I, Fraser I, Grisafi P, Fink GR (2003) Phagocytosis by neutrophils induces an amino acid deprivation response in Saccharomyces cerevisiae and Candida albicans. Proc Natl Acad Sci U S A 100:11007–11012

    PubMed Central  PubMed  CAS  Google Scholar 

  • Russell CL, Brown AJP (2005) Expression of one-hybrid fusions with Staphylococcus aureus lexA in Candida albicans confirms that Nrg1 is a transcriptional repressor and that Gcn4 is a transcriptional activator. Fungal Genet Biol 42:676–683

    PubMed  CAS  Google Scholar 

  • Sabina J, Brown V (2009) Glucose sensing network in Candida albicans: a sweet spot for fungal morphogenesis. Eukaryot Cell 8:1314–1320

    PubMed Central  PubMed  CAS  Google Scholar 

  • Sandai D, Yin Z, Selway L, Stead D, Walker J, Leach MD, Bohovych I, Ene IV, Kastora S, Budge S, Munro CA, Odds FC, Gow NA, Brown AJ (2012) The evolutionary rewiring of ubiquitination targets has reprogrammed the regulation of carbon assimilation in the pathogenic yeast Candida albicans. MBio 3. doi:10.1128/mBio.00495-12

    Google Scholar 

  • Sanglard D, Ischer F, Parkinson T, Falconer D, Bille J (2003) Candida albicans mutations in the ergosterol biosynthetic pathway and resistance to several antifungal agents. Antimicrob Agents Chemother 47:2404–2412

    PubMed Central  PubMed  CAS  Google Scholar 

  • Sellam A, Hogues H, Askew C, Tebbji F, van Het Hoog M, Lavoie H, Kumamoto CA, Whiteway M, Nantel A (2010) Experimental annotation of the human pathogen Candida albicans coding and noncoding transcribed regions using high-resolution tiling arrays. Genome Biol 11:R71. doi:10.1186/gb-2010-11-7-r71

    PubMed Central  PubMed  Google Scholar 

  • Shapiro RS, Robbins N, Cowen LE (2011) Regulatory circuitry governing fungal development, drug resistance, and disease. Microbiol Mol Biol Rev 75:213–267

    PubMed Central  PubMed  CAS  Google Scholar 

  • Sharkey LL, McNemar MD, Saporito-Irwin SM, Sypherd PS, Fonzi WA (1999) HWP1 functions in the morphological development of Candida albicans downstream of EFG1, TUP1, and RBF1. J Bacteriol 181:5273–5279

    PubMed Central  PubMed  CAS  Google Scholar 

  • Smith RL, Johnson AD (2000) Turning genes off by Ssn6-Tup1: a conserved system of transcriptional repression in eukaryotes. Trends Biochem Sci 25:325–330

    PubMed  CAS  Google Scholar 

  • Smith DA, Nicholls S, Morgan BA, Brown AJ, Quinn J (2004) A conserved stress-activated protein kinase regulates a core stress response in the human pathogen Candida albicans. Mol Biol Cell 15:4179–4190

    PubMed Central  PubMed  CAS  Google Scholar 

  • Sonneborn A, Bockmuhl DP, Ernst JF (1999a) Chlamydospore formation in Candida albicans requires the Efg1p morphogenetic regulator. Infect Immun 67:5514–5517

    PubMed Central  PubMed  CAS  Google Scholar 

  • Sonneborn A, Tebarth B, Ernst JF (1999b) Control of white-opaque phenotypic switching in Candida albicans by the Efg1p morphogenetic regulator. Infect Immun 67:4655–4660

    PubMed Central  PubMed  CAS  Google Scholar 

  • Srikantha T, Tsai LK, Daniels K, Soll DR (2000) EFG1 null mutants of Candida albicans switch but cannot express the complete phenotype of white-phase budding cells. J Bacteriol 182:1580–1591

    PubMed Central  PubMed  CAS  Google Scholar 

  • Stoldt VR, Sonneborn A, Leuker CE, Ernst JF (1997) Efg1p, an essential regulator of morphogenesis of the human pathogen Candida albicans, is a member of a conserved class of bHLH proteins regulating morphogenetic processes in fungi. EMBO J 16:1982–1991

    PubMed Central  PubMed  CAS  Google Scholar 

  • Swoboda RK, Bertram G, Delbrück S, Ernst JF, Gow NA, Gooday GW, Brown AJ (1994) Fluctuations in glycolytic mRNA levels during morphogenesis in Candida albicans reflect underlying changes in growth and are not a response to cellular dimorphism. Mol Microbiol 13:663–672

    PubMed  CAS  Google Scholar 

  • Tebarth B, Doedt T, Krishnamurthy S, Weide M, Monterola F, Dominguez A, Ernst JF (2003) Adaptation of the Efg1p morphogenetic pathway in Candida albicans by negative autoregulation and PKA-dependent repression of the EFG1 gene. J Mol Biol 329:949–962

    PubMed  CAS  Google Scholar 

  • Thevelein JM, de Winde JH (1999) Novel sensing mechanisms and targets for the cAMP-protein kinase A pathway in the yeast Saccharomyces cerevisiae. Mol Microbiol 33:904–918

    PubMed  CAS  Google Scholar 

  • Thewes S, Kretschmar M, Park H, Schaller M, Filler SG, Hube B (2007) In vivo and ex vivo comparative transcriptional profiling of invasive and non-invasive Candida albicans isolates identifies genes associated with tissue invasion. Mol Microbiol 63:1606–1628

    PubMed  CAS  Google Scholar 

  • Tobudic S, Kratzer C, Lassnigg A, Presterl E (2012) Antifungal susceptibility of Candida albicans in biofilms. Mycoses 55:199–204

    PubMed  Google Scholar 

  • Tournu H, Tripathi G, Bertram G, Macaskill S, Mavor A, Walker L, Odds FC, Gow NA, Brown AJ (2005) Global role of the protein kinase Gcn2 in the human pathogen Candida albicans. Eukaryot Cell 4:1687–1696

    PubMed Central  PubMed  CAS  Google Scholar 

  • Tripathi G, Wiltshire C, Macaskill S, Tournu H, Budge S, Brown AJ (2002) Gcn4 co-ordinates morphogenetic and metabolic responses to amino acid starvation in Candida albicans. EMBO J 21:5448–5456

    PubMed Central  PubMed  CAS  Google Scholar 

  • Ueno K, Matsumoto Y, Uno J, Sasamoto K, Sekimizu K, Kinjo Y, Chibana H (2011) Intestinal resident yeast Candida glabrata requires Cyb2p-mediated lactate assimilation to adapt in mouse intestine. PLoS One 6:e24759

    PubMed Central  PubMed  CAS  Google Scholar 

  • Uhl MA, Biery M, Craig N, Johnson AD (2003) Haploinsufficiency-based large-scale forward genetic analysis of filamentous growth in the diploid human fungal pathogen C. albicans. EMBO J 22:2668–2678

    PubMed Central  PubMed  CAS  Google Scholar 

  • Van Neil CB, Cohen AL (1942) On the metabolism of Candida albicans. J Cell Comp Physiol 20:95–112

    Google Scholar 

  • Vylkova S, Carman AJ, Danhof HA, Collette JR, Zhou H, Lorenz MC (2011) The fungal pathogen Candida albicans autoinduces hyphal morphogenesis by raising extracellular pH. MBio 2:e00055–11

    PubMed Central  PubMed  Google Scholar 

  • Walker LA, Maccallum DM, Bertram G, Gow NA, Odds FC, Brown AJ (2009) Genome-wide analysis of Candida albicans gene expression patterns during infection of the mammalian kidney. Fungal Genet Biol 46:210–219

    PubMed Central  PubMed  CAS  Google Scholar 

  • Wanke C, Eckert S, Albrecht G, van Hartingsveldt W, Punt PJ, van den Hondel CA, Braus GH (1997) The Aspergillus niger GCN4 homologue, cpcA, is transcriptionally regulated and encodes an unusual leucine zipper. Mol Microbiol 23:23–33

    PubMed  CAS  Google Scholar 

  • Wek SA, Zhu S, Wek RC (1995) The histidyl-tRNA synthetase-related sequence in the eIF-2 alpha protein kinase GCN2 interacts with tRNA and is required for activation in response to starvation for different amino acids. Mol Cell Biol 15:4497–4506

    PubMed Central  PubMed  CAS  Google Scholar 

  • Williamson MI, Samaranayake LP, MacFarlane TW (1986) Biotypes of oral Candida albicans and Candida tropicalis isolates. J Med Vet Mycol 24:81–84

    PubMed  CAS  Google Scholar 

  • Wilson D, Thewes S, Zakikhany K, Fradin C, Albrecht A, Almeida R, Brunke S, Grosse K, Martin R, Mayer F, Leonhardt I, Schild L, Seider K, Skibbe M, Slesiona S, Waechtler B, Jacobsen I, Hube B (2009) Identifying infection-associated genes of Candida albicans in the postgenomic era. FEMS Yeast Res 9:688–700

    PubMed  CAS  Google Scholar 

  • Yin Z, Wilson S, Hauser NC, Tournu H, Hoheisel JD, Brown AJ (2003) Glucose triggers different global responses in yeast, depending on the strength of the signal, transiently stabilizes ribosomal protein mRNAs. Mol Microbiol 48:713–724

    PubMed  CAS  Google Scholar 

  • Yin Z, Stead D, Selway L, Walker J, Riba-Garcia I, McLnerney T, Gaskell S, Oliver SG, Cash P, Brown AJ (2004) Proteomic response to amino acid starvation in Candida albicans and Saccharomyces cerevisiae. Proteomics 4:2425–2436

    PubMed  CAS  Google Scholar 

  • Zakikhany K, Naglik JR, Schmidt-Westhausen A, Holland G, Schaller M, Hube B (2007) In vivo transcript profiling of Candida albicans identifies a gene essential for interepithelial dissemination. Cell Microbiol 9:2938–2954

    PubMed  CAS  Google Scholar 

  • Zaragoza O, Rodriguez C, Gancedo C (2000) Isolation of the MIG1 gene from Candida albicans and effects of its disruption on catabolite repression. J Bacteriol 182:320–326

    PubMed Central  PubMed  CAS  Google Scholar 

  • Zhao R, Lockhart SR, Daniels K, Soll DR (2002) Roles of TUP1 in switching, phase maintenance, and phase-specific gene expression in Candida albicans. Eukaryot Cell 1:353–365

    PubMed Central  PubMed  CAS  Google Scholar 

  • Zhu Z, Wang H, Shang Q, Jiang Y, Cao Y, Chai Y (2012) Time course analysis of Candida albicans metabolites during biofilm development. J Proteome Res 12:2375–2385

    PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to many colleagues for stimulating debates about Candida genomics, especially our friends in the Aberdeen Fungal Group and the European FINSysB Consortium and Ken Haynes and Jan Quinn. IVE and AJPB were supported by a grant from the European Commission (PITN-GA-2008-214004). AJPB was also supported by the European Research Council (ERC-2009-AdG-249793), the U.K. Biotechnology and Biological Sciences Research Council (BBS/B/06679; BB/C510391/1; BB/D009308/1; BB/F000111/1; BB/F010826/1; BB/F00513X/1), and the Wellcome Trust (080088; 097377).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alistair J. P. Brown .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2014 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Ene, I.V., Brown, A.J.P. (2014). 14 Integration of Metabolism with Virulence in Candida albicans . In: Nowrousian, M. (eds) Fungal Genomics. The Mycota, vol 13. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-45218-5_14

Download citation