Metabolism impacts upon Candida immunogenicity and pathogenicity at multiple levels
2014; Elsevier BV; Volume: 22; Issue: 11 Linguagem: Inglês
10.1016/j.tim.2014.07.001
ISSN1878-4380
AutoresAlistair J. P. Brown, Gordon D. Brown, Mihai G. Netea, Neil A. R. Gow,
Tópico(s)Pneumocystis jirovecii pneumonia detection and treatment
Resumo•Metabolic adaptation impacts upon Candida albicans pathogenicity at multiple levels.•Carbon sources influence virulence factor expression and innate immune surveillance.•Nutrients also affect stress resistance and antifungal drug susceptibility.•Candida pathogenicity and immunogenicity therefore must differ between host niches. Metabolism is integral to the pathogenicity of Candida albicans, a major fungal pathogen of humans. As well as providing the platform for nutrient assimilation and growth in diverse host niches, metabolic adaptation affects the susceptibility of C. albicans to host-imposed stresses and antifungal drugs, the expression of key virulence factors, and fungal vulnerability to innate immune defences. These effects, which are driven by complex regulatory networks linking metabolism, morphogenesis, stress adaptation, and cell wall remodelling, influence commensalism and infection. Therefore, current concepts of Candida–host interactions must be extended to include the impact of metabolic adaptation upon pathogenicity and immunogenicity. Metabolism is integral to the pathogenicity of Candida albicans, a major fungal pathogen of humans. As well as providing the platform for nutrient assimilation and growth in diverse host niches, metabolic adaptation affects the susceptibility of C. albicans to host-imposed stresses and antifungal drugs, the expression of key virulence factors, and fungal vulnerability to innate immune defences. These effects, which are driven by complex regulatory networks linking metabolism, morphogenesis, stress adaptation, and cell wall remodelling, influence commensalism and infection. Therefore, current concepts of Candida–host interactions must be extended to include the impact of metabolic adaptation upon pathogenicity and immunogenicity. Fungal pathogens are driven by the need to assimilate nutrients, survive, and multiply. In the short term this requires the flexibility to adapt to environmental change. In the long term this has depended on the evolution of mechanisms that permit this flexibility. The outcome for the host, although being of importance to that individual, is of secondary importance to the fungal pathogen. Following dissemination to a new host, a fungal cell attempts to assimilate local nutrients, counter any local environmental stresses, and, if possible, evade any local host defences. Recent data indicate that these adaptive processes are inextricably linked. In other words, the ability of a fungal cell to counter environmental stresses and host defences is strongly influenced by its metabolic and physiological status, and hence by local nutrient availability, reinforcing the truism 'you are what you eat'. Consequently, infection outcome depends on the physiological robustness of the fungal pathogen within host niches as well as on the efficacy of host defences in these niches. The major fungal pathogen, Candida albicans, is an opportunistic pathogen that is obligately associated with warm-blooded animals [1Odds F.C. Candida and Candidosis.2nd edn. Bailliere Tindall, 1988Google Scholar]. C. albicans normally thrives as a relatively harmless commensal organism in the microbiota of the skin, the oral cavity, and the gastrointestinal (GI) and urogenital tracts of most healthy individuals [1Odds F.C. Candida and Candidosis.2nd edn. Bailliere Tindall, 1988Google Scholar, 2Calderone R.A. Clancy C.J. Candida and Candidiasis.2nd edition. ASM Press, 2012Google Scholar]. However, C. albicans infection can be triggered by perturbations of the normal microbiota (e.g., by antibiotic treatments), breaks in GI–blood barriers (e.g., as a result of injury or surgery), or by the use of medical implants (upon which C. albicans can form elaborate biofilms that seed bloodstream infection) [3Perlroth J. et al.Nosocomial fungal infections: epidemiology, diagnosis, and treatment.Med. Mycol. 2007; 45: 321-346Crossref PubMed Scopus (547) Google Scholar]. Moreover, individuals with compromised immune defences suffer the greatest risk of C. albicans infection. For example, HIV/AIDS patients are highly susceptible to oral thrush, and neutropenic patients or individuals with heritable disorders in immune signalling are highly susceptible to life-threatening systemic C. albicans infections of the blood and internal organs [3Perlroth J. et al.Nosocomial fungal infections: epidemiology, diagnosis, and treatment.Med. Mycol. 2007; 45: 321-346Crossref PubMed Scopus (547) Google Scholar, 4Brown G.D. et al.Hidden killers: human fungal infections.Sci. Transl. Med. 2012; 4: 165rv13Crossref PubMed Scopus (2705) Google Scholar]. In addition, the risk of infection is increased in diabetic patients and in those receiving parenteral nutrition [3Perlroth J. et al.Nosocomial fungal infections: epidemiology, diagnosis, and treatment.Med. Mycol. 2007; 45: 321-346Crossref PubMed Scopus (547) Google Scholar]. In the context of this review, these observations highlight two important points. First, C. albicans adapts effectively to a diverse range of host niches, including nutrient availability in these niches. Second, the probability of infection is strongly influenced by the potency of the innate immune system. We argue that these factors are interrelated. We review here current knowledge about the metabolic adaptation of C. albicans during commensalism and infection. We focus primarily on carbon source because of the pivotal role of central carbon metabolism, and because more is known about this aspect of metabolism. However, nitrogen, oxygen, phosphorus, sulphur, and micronutrient assimilation are also crucial for C. albicans pathogenicity, and many of the principles we discuss in the context of carbon are relevant to these processes. We suggest that the pivotal importance of metabolic adaptation to colonisation and disease progression extends well beyond the exploitation of available nutrients for efficient energy-generation and biomass production, and affects colonisation and disease progression at multiple levels. The development of powerful cellular, immunological, molecular, and genomic tools has empowered rapid advances in our understanding of C. albicans pathobiology, elevating this fungus to the status of a model fungal pathogen. For some time it has been clear that a defined set of virulence factors promote C. albicans pathogenicity, including yeast–hypha morphogenesis, phenotypic switching, adhesins, invasins, and secreted hydrolases [1Odds F.C. Candida and Candidosis.2nd edn. Bailliere Tindall, 1988Google Scholar, 2Calderone R.A. Clancy C.J. Candida and Candidiasis.2nd edition. ASM Press, 2012Google Scholar]. More recently the application of unbiased genome-wide screens has reminded us that multifarious fitness attributes are also crucial to C. albicans pathogenicity. These include the metabolic capacity to assimilate the host nutrients that support cell division, the resistance to physiologically relevant stresses imposed in host microenvironments, the tolerance to the elevated temperatures of the host, and the construction of a robust cell wall [5Brown A.J.P. et al.Stress responses in Candida.in: Clancy C.J. Calderone R.A. Candida and Candidiasis. 2nd edn. ASM Press, 2012: 225-242Crossref Google Scholar, 6Gow N.A.R. Hube B. Importance of the Candida albicans cell wall during commensalism and infection.Curr. Opin. Microbiol. 2012; 15: 406-412Crossref PubMed Scopus (243) Google Scholar, 7Leach M.D. et al.Hsp90 – a biological transistor that tunes cellular outputs to thermal inputs.Nat. Rev. Microbiol. 2012; 10: 693-704Crossref PubMed Scopus (75) Google Scholar, 8Brown A.J.P. et al.Stress adaptation in a pathogenic fungus.J. Exp. Biol. 2014; 217: 144-155Crossref PubMed Scopus (182) Google Scholar, 9Ene I.V. Brown A.J.P. Integration of metabolism with virulence in Candida albicans.Mycota. 2014; 13: 349-370Google Scholar]. Metabolism provides the platform upon which all other fitness attributes depend, generating the precursors and energy required for cell wall biosynthesis, antioxidant production, macromolecular repair, and protein refolding, for example. The essentiality of metabolism means that fungal specific pathways, or key enzymes with fungal specific catalytic mechanisms, represent potential targets for antifungal drug therapies [10Rodaki A. et al.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. 2006; 5: 1371-1377Crossref PubMed Scopus (68) Google Scholar, 11Xu D. et al.Chemical genetic profiling and characterization of small-molecule compounds that affect the biosynthesis of unsaturated fatty acids in Candida albicans.J. Biol. Chem. 2009; 284: 19754-19764Crossref PubMed Scopus (57) Google Scholar]. C. albicans cells display efficient metabolic adaptation to host microenvironments, rapidly tuning their metabolism to the available nutrients. These microenvironments are complex, dynamic, and often glucose-limited. For example, glucose levels are maintained at around 0.06–0.1% (3–5 mM) in the bloodstream, and are around 0.5% in vaginal secretions [12Barelle C.J. et al.Niche-specific regulation of central metabolic pathways in a fungal pathogen.Cell. Microbiol. 2006; 8: 961-971Crossref PubMed Scopus (249) Google Scholar, 13Owen D.H. Katz D.F. A vaginal fluid simulant.Contraception. 1999; 59: 91-95Abstract Full Text Full Text PDF PubMed Scopus (551) Google Scholar]. Consequently, the expression of key metabolic functions is controlled in a niche-specific fashion during host colonisation, commensalism, and disease progression [12Barelle C.J. et al.Niche-specific regulation of central metabolic pathways in a fungal pathogen.Cell. Microbiol. 2006; 8: 961-971Crossref PubMed Scopus (249) Google Scholar, 14Brown A.J.P. et al.Infection-related gene expression in Candida albicans.Curr. Opin. Microbiol. 2007; 10: 307-313Crossref PubMed Scopus (118) Google Scholar, 15Whittington A. et al.From commensal to pathogen: Candida albicans.Mycota. 2014; 12: 3-18Google Scholar] (Table 1). C. albicans cells induce glycolytic, tricarboxylic acid cycle, and fatty acid β-oxidation genes during mucosal invasion [16Zakikhany K. et al.In vivo transcript profiling of Candida albicans identifies a gene essential for interepithelial dissemination.Cell. Microbiol. 2007; 9: 2938-2954Crossref PubMed Scopus (231) Google Scholar, 17Wilson D. et al.Identifying infection-associated genes of Candida albicans in the postgenomic era.FEMS Yeast Res. 2009; 9: 688-700Crossref PubMed Scopus (96) Google Scholar]. In the bloodstream and during renal infection, C. albicans populations are heterogeneous, individual cells displaying glycolytic activity (hexose catabolism) or gluconeogenic activity (hexose anabolism), depending upon their immediate microenvironments [12Barelle C.J. et al.Niche-specific regulation of central metabolic pathways in a fungal pathogen.Cell. Microbiol. 2006; 8: 961-971Crossref PubMed Scopus (249) Google Scholar, 18Fradin C. et al.Stage-specific gene expression of Candida albicans in human blood.Mol. Microbiol. 2003; 47: 1523-1543Crossref PubMed Scopus (190) Google Scholar, 19Fradin C. et al.Granulocytes govern the transcriptional response, morphology and proliferation of Candida albicans in human blood.Mol. Microbiol. 2005; 56: 397-415Crossref PubMed Scopus (361) Google Scholar]. Following phagocytosis by macrophages and neutrophils, C. albicans cells display expression patterns that reflect carbon starvation, activating enzymes involved in fatty acid β-oxidation, the glyoxylate cycle, and gluconeogenesis [19Fradin C. et al.Granulocytes govern the transcriptional response, morphology and proliferation of Candida albicans in human blood.Mol. Microbiol. 2005; 56: 397-415Crossref PubMed Scopus (361) Google Scholar, 20Lorenz M.C. et al.Transcriptional response of Candida albicans upon internalization by macrophages.Eukaryot. Cell. 2004; 3: 1076-1087Crossref PubMed Scopus (567) Google Scholar, 21Rubin-Bejerano I. et al.Phagocytosis by neutrophils induces an amino acid deprivation response in Saccharomyces cerevisiae and Candida albicans.Proc. Natl. Acad. Sci. U.S.A. 2003; 100: 11007-11012Crossref PubMed Scopus (178) Google Scholar]. Lactic acid metabolism is essential for GI colonisation [22Ueno K. et al.Intestinal resident yeast Candida glabrata requires Cyb2p-mediated lactate assimilation to adapt in mouse intestine.PLoS ONE. 2011; 6: e24759Crossref PubMed Scopus (85) Google Scholar], and this non-fermentable carboxylic acid is present at significant concentrations in the vagina (∼0.4%: 45 mM) [13Owen D.H. Katz D.F. A vaginal fluid simulant.Contraception. 1999; 59: 91-95Abstract Full Text Full Text PDF PubMed Scopus (551) Google Scholar]. Therefore, C. albicans cells thrive in host microenvironments that contain contrasting carbon sources.Table 1Candida albicans carbon metabolism in host nichesGene regulationaUpregulation (red arrows), downregulation (blue arrows), and no significant regulation (grey arrows) are expressed relative to the control C. albicans cells used in each transcript profiling experiment. Upregulation or downregulation is inferred on the availability of data for some (not all) of the genes on these pathways. These expression patterns display temporal regulation.Host nicheGlycolysisGluconeogenesisGlyoxylate cycleFatty acid β-oxidationRefsBlood plasma19Fradin C. et al.Granulocytes govern the transcriptional response, morphology and proliferation of Candida albicans in human blood.Mol. Microbiol. 2005; 56: 397-415Crossref PubMed Scopus (361) Google ScholarNeutrophils12Barelle C.J. et al.Niche-specific regulation of central metabolic pathways in a fungal pathogen.Cell. Microbiol. 2006; 8: 961-971Crossref PubMed Scopus (249) Google Scholar, 17Wilson D. et al.Identifying infection-associated genes of Candida albicans in the postgenomic era.FEMS Yeast Res. 2009; 9: 688-700Crossref PubMed Scopus (96) Google Scholar, 19Fradin C. et al.Granulocytes govern the transcriptional response, morphology and proliferation of Candida albicans in human blood.Mol. Microbiol. 2005; 56: 397-415Crossref PubMed Scopus (361) Google Scholar, 21Rubin-Bejerano I. et al.Phagocytosis by neutrophils induces an amino acid deprivation response in Saccharomyces cerevisiae and Candida albicans.Proc. Natl. Acad. Sci. U.S.A. 2003; 100: 11007-11012Crossref PubMed Scopus (178) Google Scholar, 56Miramon P. et al.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. 2012; 7: e52850Crossref PubMed Scopus (88) Google Scholar; Mette Jacobsen, PhD thesis, Aberdeen University, 2005Macrophages12Barelle C.J. et al.Niche-specific regulation of central metabolic pathways in a fungal pathogen.Cell. Microbiol. 2006; 8: 961-971Crossref PubMed Scopus (249) Google Scholar, 20Lorenz M.C. et al.Transcriptional response of Candida albicans upon internalization by macrophages.Eukaryot. Cell. 2004; 3: 1076-1087Crossref PubMed Scopus (567) Google Scholar; Mette Jacobsen, PhD thesis, Aberdeen University, 2005Oral mucosa16Zakikhany K. et al.In vivo transcript profiling of Candida albicans identifies a gene essential for interepithelial dissemination.Cell. Microbiol. 2007; 9: 2938-2954Crossref PubMed Scopus (231) Google Scholar, 17Wilson D. et al.Identifying infection-associated genes of Candida albicans in the postgenomic era.FEMS Yeast Res. 2009; 9: 688-700Crossref PubMed Scopus (96) Google ScholarKidneybPopulation heterogeneity in the expression patterns is observed by single cell profiling, presumably because of variability in the availability of host carbon sources between immediate cellular microenvironments and the local consumption of these carbon sources by the invading fungus.////12Barelle C.J. et al.Niche-specific regulation of central metabolic pathways in a fungal pathogen.Cell. Microbiol. 2006; 8: 961-971Crossref PubMed Scopus (249) Google Scholar, Mette Jacobsen, PhD thesis, Aberdeen University, 2005LivercThe upregulation of genes involved in both hexose catabolism and anabolism in these transcript profiling experiments could be due to the population heterogeneity of C. albicans cells colonising the liver.17Wilson D. et al.Identifying infection-associated genes of Candida albicans in the postgenomic era.FEMS Yeast Res. 2009; 9: 688-700Crossref PubMed Scopus (96) Google Scholar, 58Thewes S. et al.In vivo and ex vivo comparative transcriptional profiling of invasive and non-invasive Candida albicans isolates identifies genes associated with tissue invasion.Mol. Microbiol. 2007; 63: 1606-1628Crossref PubMed Scopus (124) Google Scholara Upregulation (red arrows), downregulation (blue arrows), and no significant regulation (grey arrows) are expressed relative to the control C. albicans cells used in each transcript profiling experiment. Upregulation or downregulation is inferred on the availability of data for some (not all) of the genes on these pathways. These expression patterns display temporal regulation.b Population heterogeneity in the expression patterns is observed by single cell profiling, presumably because of variability in the availability of host carbon sources between immediate cellular microenvironments and the local consumption of these carbon sources by the invading fungus.c The upregulation of genes involved in both hexose catabolism and anabolism in these transcript profiling experiments could be due to the population heterogeneity of C. albicans cells colonising the liver. Open table in a new tab Metabolic adaptation is controlled by complex transcriptional networks in C. albicans [9Ene I.V. Brown A.J.P. Integration of metabolism with virulence in Candida albicans.Mycota. 2014; 13: 349-370Google Scholar, 23Askew C. et al.Transcriptional regulation of carbohydrate metabolism in the human pathogen Candida albicans.PLoS Pathog. 2009; 5: e1000612Crossref PubMed Scopus (185) Google Scholar, 24Lavoie H. et al.Evolutionary tinkering with conserved components of a transcriptional regulatory network.PLoS Biol. 2010; 8: e1000329Crossref PubMed Scopus (109) Google Scholar]. The cellular roles of some of these networks have been conserved during yeast evolution, such as the general control of amino acid metabolism (GCN response) [9Ene I.V. Brown A.J.P. Integration of metabolism with virulence in Candida albicans.Mycota. 2014; 13: 349-370Google Scholar, 25Tripathi G. et al.CaGcn4 co-ordinates morphogenetic and metabolic responses to amino acid starvation in Candida albicans.EMBO J. 2002; 21: 5448-5456Crossref PubMed Scopus (163) Google Scholar] and sugar-sensing pathways [26Sabina J. Brown V. Glucose sensing network in Candida albicans: a sweet spot for fungal morphogenesis.Eukaryot. Cell. 2009; 8: 1314-1320Crossref PubMed Scopus (62) Google Scholar]. Interestingly, the regulation of central carbon metabolism has undergone major transcriptional rewiring in C. albicans relative to Saccharomyces cerevisiae. For example, glycolysis is induced by Gcr1 in S. cerevisiae, but by Gal4 and Tye7 in C. albicans [9Ene I.V. Brown A.J.P. Integration of metabolism with virulence in Candida albicans.Mycota. 2014; 13: 349-370Google Scholar, 23Askew C. et al.Transcriptional regulation of carbohydrate metabolism in the human pathogen Candida albicans.PLoS Pathog. 2009; 5: e1000612Crossref PubMed Scopus (185) Google Scholar, 24Lavoie H. et al.Evolutionary tinkering with conserved components of a transcriptional regulatory network.PLoS Biol. 2010; 8: e1000329Crossref PubMed Scopus (109) Google Scholar]. The importance of metabolic adaptation for GI colonisation and systemic infection has been highlighted by the elaboration of regulatory networks that are required for these processes in C. albicans. In vivo genetic screens have indicated that Tye7 (a glycolytic activator) is specifically required for GI colonisation, whereas Rtg1/3 and Hms1 (which modulate hexose catabolism) promote both GI colonisation and systemic infection [27Perez J.C. et al.Candida albicans commensalism and pathogenicity are intertwined traits directed by a tightly knit transcriptional regulatory circuit.PLoS Biol. 2013; 11: e1001510Crossref PubMed Scopus (116) Google Scholar]. Metabolic adaptation within host niches is linked in part to the morphological states of the fungus in these niches, such as yeast, pseudohyphal, and hyphal cells, white and opaque cells, and the recently described GUT ('Gastrointestinally-indUced Transition') phenotype [28Pande K. et al.Passage through the mammalian gut triggers a phenotypic switch that promotes Candida albicans commensalism.Nat. Genet. 2013; 45: 1088-1091Crossref PubMed Scopus (226) Google Scholar, 29Lan C.Y. et al.Metabolic specialization associated with phenotypic switching in Candida albicans.Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 14907-14912Crossref PubMed Scopus (222) Google Scholar, 30Nantel A. et al.Transcript profiling of Candida albicans cells undergoing the yeast-to-hyphal transition.Mol. Biol. Cell. 2002; 13: 3452-3465Crossref PubMed Scopus (301) Google Scholar]. Nevertheless, metabolic adaptation is integral to C. albicans commensalism and pathogenicity. Metabolism also promotes the virulence of C. albicans indirectly by enhancing stress adaptation. Stress resistance is required for C. albicans virulence: it increases the survival of fungal cells in host niches by reducing their vulnerability to local environmental stresses and to phagocytic killing [5Brown A.J.P. et al.Stress responses in Candida.in: Clancy C.J. Calderone R.A. Candida and Candidiasis. 2nd edn. ASM Press, 2012: 225-242Crossref Google Scholar, 31Arana D.M. et al.Differential susceptibility of mitogen-activated protein kinase pathway mutants to oxidative-mediated killing by phagocytes in the fungal pathogen Candida albicans.Cell. Microbiol. 2007; 9: 1647-1659Crossref PubMed Scopus (86) Google Scholar, 32Patterson M.J. et al.Ybp1 and Gpx3 signaling in Candida albicans govern hydrogen peroxide-induced oxidation of the Cap1 transcription factor and macrophage escape.Antiox. Redox Signal. 2013; 19: 2244-2260Crossref PubMed Scopus (59) Google Scholar]. Metabolism contributes to stress adaptation by generating molecules such as the osmolyte glycerol, antioxidants such as glutathione, and the stress protectant trehalose [5Brown A.J.P. et al.Stress responses in Candida.in: Clancy C.J. Calderone R.A. Candida and Candidiasis. 2nd edn. ASM Press, 2012: 225-242Crossref Google Scholar]. Therefore, the ability of C. albicans cells to respond to environmental stress is likely to depend upon the preadapted metabolic state of these cells, and hence upon available nutrients in host microenvironments. Almost without exception, however, the analysis of C. albicans stress responses has been performed on cells cultured on rich, glucose-containing media [5Brown A.J.P. et al.Stress responses in Candida.in: Clancy C.J. Calderone R.A. Candida and Candidiasis. 2nd edn. ASM Press, 2012: 225-242Crossref Google Scholar] that differ significantly from host microenvironments which are often glucose-limited (above). Significantly, recent data indicate that changes in carbon source exert dramatic effects upon the stress resistance of C. albicans [33Ene I.V. et al.Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen.Cell. Microbiol. 2012; 14: 1319-1335Crossref PubMed Scopus (214) Google Scholar, 34Rodaki A. et al.Glucose promotes stress resistance in the fungal pathogen, Candida albicans.Mol. Biol. Cell. 2009; 20: 4845-4855Crossref PubMed Scopus (135) Google Scholar]. Transient exposure to glucose induces the transcription of C. albicans genes involved in oxidative stress adaptation, thereby enhancing cellular resistance to acute oxidative stress [34Rodaki A. et al.Glucose promotes stress resistance in the fungal pathogen, Candida albicans.Mol. Biol. Cell. 2009; 20: 4845-4855Crossref PubMed Scopus (135) Google Scholar]. This phenomenon, which is regulated by glucose-sensing pathways, probably reflects adaptive prediction [35Mitchell A. et al.Adaptive prediction of environmental changes by microorganisms.Nature. 2009; 460: 220-224Crossref PubMed Scopus (382) Google Scholar] whereby C. albicans has 'learnt' over evolutionary time to anticipate phagocytic attack following entry to the bloodstream [8Brown A.J.P. et al.Stress adaptation in a pathogenic fungus.J. Exp. Biol. 2014; 217: 144-155Crossref PubMed Scopus (182) Google Scholar]. Interestingly, the contrasting evolutionary pressures experienced by C. albicans and its relatively benign cousin S. cerevisiae have yielded contrasting predictive stress responses to glucose. Glucose enhances oxidative stress resistance in C. albicans, whereas it decreases stress resistance in S. cerevisiae via protein kinase A (PKA)-mediated repression of the core transcriptional response to stress [36Garreau H. et al.Hyperphosphorylation of Msn2 and Msn4 in response to heat shock and the diauxic shift is inhibited by cAMP in Saccharomyces cerevisiae.Microbiology. 2000; 146: 2113-2120Crossref PubMed Scopus (115) Google Scholar, 37Gasch A.P. et al.Genomic expression programs in the response of yeast cells to environmental changes.Mol. Biol. Cell. 2000; 11: 4241-4257Crossref PubMed Scopus (3763) Google Scholar]. The differing effects of glucose in these yeasts are largely due to the functional rewiring of Msn2/4 transcription factors, which activate this core stress response in S. cerevisiae and Candida glabrata [37Gasch A.P. et al.Genomic expression programs in the response of yeast cells to environmental changes.Mol. Biol. Cell. 2000; 11: 4241-4257Crossref PubMed Scopus (3763) Google Scholar, 38Roetzer A. et al.Candida glabrata environmental stress response involves Saccharomyces cerevisiae Msn2/4 orthologous transcription factors.Mol. Microbiol. 2008; 69: 603-620Crossref PubMed Scopus (100) Google Scholar], but control weak acid stress responses in C. albicans [39Ramsdale M. et al.The novel gene MNL1 regulates weak acid induced stress responses of the fungal pathogen Candida albicans.Mol. Biol. Cell. 2008; 19: 4393-4403Crossref PubMed Scopus (61) Google Scholar]. Carbon adaptation also affects resistance to osmotic stress and antifungal drugs [33Ene I.V. et al.Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen.Cell. Microbiol. 2012; 14: 1319-1335Crossref PubMed Scopus (214) Google Scholar, 40Ene I.V. et al.Carbon source-induced reprogramming of the cell wall proteome and secretome modulates the adherence and drug resistance of the fungal pathogen Candida albicans.Proteomics. 2012; 12: 3164-3179Crossref PubMed Scopus (123) Google Scholar]. These effects, which are mediated partly through PKA signalling [41Giacometti R. et al.Catalytic isoforms Tpk1 and Tpk2 of Candida albicans PKA have non-redundant roles in stress response and glycogen storage.Yeast. 2009; 26: 273-285Crossref PubMed Scopus (43) Google Scholar], may relate to the effects of metabolic adaptation upon the cellular abundances of osmolytes such as glycerol, and antioxidants such as glutathione and trehalose [34Rodaki A. et al.Glucose promotes stress resistance in the fungal pathogen, Candida albicans.Mol. Biol. Cell. 2009; 20: 4845-4855Crossref PubMed Scopus (135) Google Scholar, 42Gonzalez-Parraga P. et al.Role of antioxidant enzymatic defences against oxidative stress H2O2 and the acquisition of oxidative tolerance in Candida albicans.Yeast. 2003; 20: 1161-1169Crossref PubMed Scopus (83) Google Scholar, 43Gonzalez-Parraga P. et al.Adaptive tolerance to oxidative stress and the induction of antioxidant enzymatic activities in Candida albicans are independent of the Hog1 and Cap1-mediated pathways.FEMS Yeast Res. 2010; 10: 747-756Crossref PubMed Scopus (29) Google Scholar]. Glycerol and trehalose are synthesised via short metabolic branches off the glycolytic pathway. However, these effects also involve C. albicans cell wall remodelling [33Ene I.V. et al.Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen.Cell. Microbiol. 2012; 14: 1319-1335Crossref PubMed Scopus (214) Google Scholar, 40Ene I.V. et al.Carbon source-induced reprogramming of the cell wall proteome and secretome modulates the adherence and drug resistance of the fungal pathogen Candida albicans.Proteomics. 2012; 12: 3164-3179Crossref PubMed Scopus (123) Google Scholar]. Growth on different carbon sources yields C. albicans cells with cell walls that differ architecturally and biophysically (below). These preadapted cell walls confer cells with differing abilities to survive the imposition of osmotic and cell wall stresses. For example, compared with cells grown on glucose, lactate-grown cells display increased resistance to osmotic stress, amphotericin B, and caspofungin, and reduced resistance to an azole antifungal drug [33Ene I.V. et al.Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen.Cell. Microbiol. 2012; 14: 1319-1335Crossref PubMed Scopus (214) Google Scholar]. These alterations, which have been observed for a range of carbon sources including other sugars (fructose and galactose), other carboxylic acids (pyruvate), lipids, and amino acids [33Ene I.V. et al.Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen.Cell. Microbiol. 2012; 14: 1319-1335Crossref PubMed Scopus (214) Google Scholar], correlate with carbon source-mediated changes in the cell wall proteome [40Ene I.V. et al.Carbon source-induced reprogramming of the cell wall proteome and secretome modula
Referência(s)