Advertisement

Environmental Stress-Sensing and Pathogenicity in Cryptococcus neoformans

  • Man-Shun Fu
  • Rebecca A. Hall
  • Fritz A. Mühlschlegel
Chapter
Part of the The Yeast Handbook book series (YEASTHDB)

Abstract

Cellular stress can be defined as the damage caused to macromolecular systems when the cell is exposed to acute environmental changes, while a stress response is a conserved mechanism of resistance to these damages (Kültz 2003). Cryptococcus neoformans, like most pathogens, not only has to cope with substantial changes in its natural environment, but must also respond and proliferate in a variety of conditions found within the host. As with most pathogenic microbes therefore, appropriate responses to stress are key elements for survival in the host. The stresses C. neoformans encounters within its host include oxidative stress, nitrosative stress, osmotic shock, high temperature, hypoxia, nutrient deprivation, changes in pH, low- calcium and iron deprivation (Brown et al. 2007). Several signaling pathways mediated by the Hog1p, protein kinase C (pkC) and calcineurin/calmodulin allow this fungus to sense and respond to stress. However, the mechanisms underlying stress responses in C. neoformans are not completely understood. Recent genomic and proteomic approaches have allowed us to gain further understanding of the stress responses in C. neoformans. In this chapter, the current knowledge on individual genes, pathways and transcription factors which are essential for stress resistance in C. neoformans are discussed.

Keywords

Histidine Kinase Nitrosative Stress Heat Shock Transcription Factor Cumene Hydroperoxide Iron Deprivation 
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.

Notes

Acknowledgments

We apologize to our colleagues for their important work that could not be cited due to restrictions on space. We would like to thank Shirelle Burton-Fanning for critically reading the manuscript. MSF is funded by a University of Kent-Hong Kong PhD studentship. RAH is a Postdoctoral Research Assistant funded by the MRC. Work in the FAM laboratory is funded by the MRC and BBSRC.

References

  1. Akhter S, McDade HC, Gorlach JM, Heinrich G, Cox GM, Perfect JR (2003) Role of alternative oxidase gene in pathogenesis of Cryptococcus neoformans. Infect Immun 71:5794–5802CrossRefPubMedGoogle Scholar
  2. Alspaugh JA, Perfect JR, Heitman J (1997) Cryptococcus neoformans mating and virulence are regulated by the G-protein alpha subunit GPA1 and cAMP. Genes Dev 11:3206–3217CrossRefPubMedGoogle Scholar
  3. Alspaugh JA, Pukkila-Worley R, Harashima T, Cavallo LM, Funnel D, Cox GM, Perfect JR, Kronstad JW, Heitman J (2002) Adenylyl cyclase functions downstream of the G-alpha protein GPA1 and controls mating and pathogenicity of Cryptococcus neoformans. Eukaryotic Cell 1:75–84CrossRefPubMedGoogle Scholar
  4. Arakane Y, Muthukrishnan S, Beeman RW, Kanost MR, Kramer KJ (2005) Laccase 2 is the phenolocidase gene required for beetle cuticle tanning. Proc Natl Acad Sci USA 102:11337–11342CrossRefPubMedGoogle Scholar
  5. Bahn YS (2008) Master and commander in fungal pathogens: the two-component system and the HOG signaling pathway. Eukaryotic Cell 7:2017–2036CrossRefPubMedGoogle Scholar
  6. Bahn YS, Kojima K, Cox GM, Heitman J (2005) Specialization of the HOG pathway and its impact on differentiation and virulence of Cryptococcus neoformans. Mol Biol Cell 16:2285–2300CrossRefPubMedGoogle Scholar
  7. Bahn YS, Kojima K, Cox GM, Heitman J (2006) A unique fungal two-component system regulates stress responses, drug sensitivity, sexual development, and virulence of Cryptococcus neoformans. Mol Biol Cell 17:3122–3135CrossRefPubMedGoogle Scholar
  8. Bahn YS, Geunes-Boyer S, Heitman J (2007) Ssk2 mitogen-actiated protein kinase kinase kinase governs divergent patterns of the stress-activated Hog1 signaling pathway in Cryptococcus neoformans. Eukaryotic Cell 6:2278–2289CrossRefPubMedGoogle Scholar
  9. Blankenship JR, Mitchell AP (2006) How to build a biofilm: a fungal perspective. Curr Opin Microbiol 9:588–594CrossRefPubMedGoogle Scholar
  10. Bose I, Reese AJ, Ory JJ, Janbon G, Doering TL (2003) A yeast under cover: the capsule of Cryptococcus neoformans. Eukaryotic Cell 2:655–663CrossRefPubMedGoogle Scholar
  11. Braun BR, Kadosh D, Johnson AD (2001) NRG1, a repressor of filamentous growth in C. albicans, is down-regulated during filament induction. EMBO J 20:4753–4761CrossRefPubMedGoogle Scholar
  12. Brown SM, Campbell LT, Lodge JK (2007) Cryptococcus neoformans, a fungus under stress. Curr Opin Microbiol 10:320–325CrossRefPubMedGoogle Scholar
  13. Buchanan KL, Murphy JW (1998) What makes Cryptococcus neoformans a pathogen? Emerging infectious diseases 4:71–83Google Scholar
  14. Casadevall A, Rosas AL, Nosanchuk JD (2000) Melanin and virulence in Cryptococcus neoformans. Curr Opin Microbiol 3:354–358CrossRefPubMedGoogle Scholar
  15. Coenjaerts FEJ, Hoepelman AIM, Scharringa J, Aarts M, Ellerbroek PM, Bevaart L, van Strijp JAG, Janbon G (2006) The Skn7 response regulator of Cryptococcus neoformans is involved in oxidative stress signalling and augments intracellular survival in endothelium. FEMS Yeast Res 6:652–661CrossRefPubMedGoogle Scholar
  16. Cox GM, Harrison TS, McDade HC, Taborda CP, Heinrich G, Casadevall A, Perfect JR (2003) Superoxide dismutase influences the virulence of Cryptococcus neoformans by affecting growth within macrophages. Infect Immun 71:173–180CrossRefPubMedGoogle Scholar
  17. Cramer KL, Gerrald QD, Nichols CB, Price MS, Alspaugh JA (2006) Transcription factor Nrg1 mediates capsule formation, stress response, and pathogenesis in Cryptococcus neoformans. Eukaryotic Cell 5:1147–1156CrossRefPubMedGoogle Scholar
  18. Crowe JH (2007) Trehalose as a ‘chemical chaperone’: fact and fantasy. Adv Exp Med Biol 594:143–158CrossRefPubMedGoogle Scholar
  19. D’Souza CA, Alspaugh JA, Yue C, Harashima T, Cox GM, Perfect JR, Heitman J (2001) Cyclic-AMP-dependent protein kinase controls virulence of the fungal pathogen C. neoformans. Mol Cell Biol 21:3179–3191CrossRefPubMedGoogle Scholar
  20. de Jesus-Berrios M, Liu L, Nussbaum JC, Cox GM, Stamler JS, Heitman J (2003) Enzymes that counteract nitrosative stress promote fungal virulence. Curr Biol 13:1983–1988Google Scholar
  21. Gerik KJ, Donlin MJ, Soto CE, Banks AM, Banks IR, Maligie MA, Selitrennikoff CP, Lodge JK (2005) Cell wall integrity is dependent on the PKC1 signal transduction pathway in Cryptococcus neoformans. Mol Microbiol 58:393–408CrossRefPubMedGoogle Scholar
  22. Gerik KJ, Bhimireddy SR, Ryerse JS, Specht CA, Lodge JK (2008) PKC1 is essential for protection against both oxidative and nitrosative stresses, cell integrity, and normal manifestation of virulence factors in the pathogenic fungus Cryptococcus neoformans. Eukaryotic Cell 7:1685–1698CrossRefPubMedGoogle Scholar
  23. Giles SS, Bainić-Haberle I, Perfect JR, Cox GM (2005) Cryptococcus neoformans mitochondrial superoxide dismutase: an essential link between antioxidant function and high-temperature growth. Eukaryotic Cell 4:46–54CrossRefPubMedGoogle Scholar
  24. Howard DH (1999) Acquisition, transport, and storage of iron by pathogenic fungi. Clin Microbiol Rev 12:394–404PubMedGoogle Scholar
  25. Hu G, Steen BR, Lian T, Sham AP, Tam N, Tangen KL, Kronstad JW (2007) Transcriptional regulation by protein kinase A in Cryptococcus neoformans. PloS Pathog 3:1–17CrossRefGoogle Scholar
  26. Hull CM, Heitman J (2002) Genetics of Cryptococcus neoformans. Annu Rev Genet 36:557–615CrossRefPubMedGoogle Scholar
  27. Janbon G (2004) Cryptococcus neoformans capsule biosynthesis and regulation. FEMS Yeast Res 4:765–771CrossRefPubMedGoogle Scholar
  28. Jung WH, Sham A, White R, Kronstad JW (2006) Iron regulation of the major virulence factors in the AIDS-associated pathogen Cryptococcus neoformans. PLoS Biol 4:2282–2294CrossRefGoogle Scholar
  29. Kojima K, Bahn YS, Heitman J (2006) Calcineurin, Mpk1 and Hog1 MAPK pathways independently control fludioxonil antifungal sensitivity in Cryptococcus neoformans. Microbiology 152:591–604CrossRefPubMedGoogle Scholar
  30. Kraus PR, Heitman J (2003) Coping with stress: calmodulin and calcineurin in model and pathogenic fungi. Biochem Biophys Res Commun 311:1151–1157CrossRefPubMedGoogle Scholar
  31. Kraus PR, Fox DS, Cox GM, Heitman J (2003) The Cryptococcus neoformans MAP kinase Mpk1 regulates cell integrity in response to antifungal drugs and loss of calcineurin function. Mol Microbiol 48:1366–1387CrossRefGoogle Scholar
  32. Kraus PR, Nichols CB, Heitman J (2005) Calcium-calcineurin-independent roles for calmodulin in Cryptococcus neoformans morphogenesis and high-temperature growth. Eukaryotic Cell 4:1079–1087CrossRefPubMedGoogle Scholar
  33. Kültz D (2003) Evolution of the cellular stress proteome: from monophyletic origin to ubiquitous function. J Exp Biol 206:3119–3124CrossRefPubMedGoogle Scholar
  34. Lian T, Simmer MI, D’Souza CA, Steen BR, Zuyderduyn SD, Jones SJM, Marra MA, Kronstad JW (2005) Iron-regulated transcription and capsule formation in the fungal pathogen Cryptococcus neoformans. Mol Microbiol 55:1452–1472CrossRefPubMedGoogle Scholar
  35. Liu M, Du P, Heinrich G, Cox GM, Gelli A (2006) Cch1 mediates calcium entry in Cryptococcus neoformans and its essential in low-calcium environments. Eukaryotic Cell 5:1788–1796CrossRefPubMedGoogle Scholar
  36. Martinez LR, Casadevall A (2005) Specific antibody can prevent fungal biofilm formation and this effect correlates with protective efficacy. Infect Immun 73:6350–6362CrossRefPubMedGoogle Scholar
  37. Martinez LR, Casadevall A (2007) Cryptococcus neoformans biofilm formation depends on surface support and carbon source and reduces fungal cell susceptibility to heat, cold and UV light. Appl Environ Microbiol 73:4592–4601CrossRefPubMedGoogle Scholar
  38. Mayer A, Staples R (2002) Laccase: new functions for an old enzyme. Phytochemistry 60:551–565CrossRefPubMedGoogle Scholar
  39. Missall TA, Lodge JK (2005) Function of the thioredoxin proteins in Cryptococcus neoformans during stress or virulence and regulation by putative transcriptional modulators. Mol Microbiol 57:847–858CrossRefPubMedGoogle Scholar
  40. Missall TA, Pusateri ME, Lodge JK (2004) Thiol peroxidase is critical for virulence and resistance to nitric oxide and peroxide in the fungal pathogen, Cryptococcus neoformans. Mol Microbiol 5:1447–1458CrossRefGoogle Scholar
  41. Missall TA, Cherry-Harris JF, Lodge JK (2005a) Two glutathione peroxidases in the fungal pathogen Cryptococcus neoformans are expressed in the presence of specific substrates. Microbiology 151:2573–2581CrossRefPubMedGoogle Scholar
  42. Missall TA, Moran JM, Corbett JA, Lodge JK (2005b) Distinct stress responses of two functional laccases in Cryptococcus neoformans are revealed in the absence of the thiol-specific antioxidant Tsa1. Eukaryotic Cell 4:202–208CrossRefPubMedGoogle Scholar
  43. 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 (2001) NRG1 represses yeast-hyphae morphogenesis and hyphae-specific gene expression in Candida albicans. EMBO J 20:4742–4752CrossRefPubMedGoogle Scholar
  44. Nyhus KJ, Wilborn AT, Jacobson ES (1997) Ferric iron reduction by Cryptococcus neoformans. Infect Immun 65:434–438PubMedGoogle Scholar
  45. Odom A, Muir S, Lim E, Toffaltti DL, Perfect J, Heitman J (1997) Calcineurin is required for virulence of Cryptococcus neoformans. EMBO J 16:2576–2589CrossRefPubMedGoogle Scholar
  46. Petzold EW, Himmelreich U, Mylonakis E, Rude T, Toffaletti D, Cox GM, Miller JL, Perfect JR (2006) Characterization and regulation of the trehalose synthesis pathway and its importance in the pathogenicity of Cryptococcus neoformans. Infect Immun 74:5877–5887CrossRefPubMedGoogle Scholar
  47. Posas F, Wurgler-Murphy SM, Maeda T, Witten EA, Thai TC, Saito H (1996) Yeast HOG1 MAP kinase cascade is regulated by a multistep phosphorelay mechanism in the SLN1-YPD1-SSK1 “two-component” osmosensor. Cell 86:865–875CrossRefPubMedGoogle Scholar
  48. Pukkila-Worley R, Alspaugh JA (2004) Cyclic AMP signaling in Cryptococcus neoformans. FEMS Yeast Res 4:361–367CrossRefPubMedGoogle Scholar
  49. Sales SD, Bennett JE, Kwon-Chung KJ, Perfect JR, Williamson PR (1996) Effect of the laccase gene, CNLAC1, on virulence of Cryptococcus neoformans. J Exp Med 184:377–386CrossRefGoogle Scholar
  50. Sanglard D, Ischer F, Marchetti O, Entenza J, Bille J (2003) Calcineurin A of Candida albicans: involvement in antifungal tolerance, cell morphogenesis and virulence. Mol Microbiol 48:959–976CrossRefPubMedGoogle Scholar
  51. Stewart EJ, Aslund F, Beckwith J (1998) Disulfide bond formation in the Escherichia coli cytoplasm: an in vivo role reversal for the thioredoxins. EMBO J 17:5543–5550CrossRefPubMedGoogle Scholar
  52. Tangen KL, Jung WH, Sham AP, Lain T, Kronstad JW (2007) The iron- and cAMP-regulated gene SIT1 influences ferrioxamine B utilization, melanization and cell wall structure in Cryptococcus neoformans. Microbiology 153:29–41CrossRefPubMedGoogle Scholar
  53. Tolkacheva T, McNamara TP, Piekarz E, Courchesne W (1994) Cloning of a Cryptococcus neoformans gene, GPA1, encoding a G-protein K-subunit homolog. Infect Immun 62:2849–2856PubMedGoogle Scholar
  54. Vyas VK, Berkey CD, Miyao T, Carlson M (2005) Repressors Nrg1 and Nrg2 regulate a set of stress-responsive genes in Saccharomyces cerevisiae. Eukaryotic Cell 4:1882–1891CrossRefPubMedGoogle Scholar
  55. Wang Y, Casadevall A (1994) Susceptibility of melanized and non-melanized Cryptococcus neoformans to nitrogen- and oxygen-derived oxidants. Infect Immun 62:3004–3007PubMedGoogle Scholar
  56. Wang P, Heitman J (2005) The cyclophilins. Genome Biol 6:2261–2266CrossRefGoogle Scholar
  57. Zaragoza O, Chrisman CJ, Castelli MV, Frases S, Cuenca-Estrella M, Rodríguez-Tudela J, Casadevall A (2008) Capsule enlargement in Cryptococcus neoformans confers resistance to oxidative stress suggesting a mechanism for intracellular survival. Cell Microbiol 10: 2043–2057CrossRefPubMedGoogle Scholar
  58. Zhang S, Hacham M, Panepinto J, Hu G, Shin S, Zhu X, Williamson PR (2006) The Hsp70 member, Ssa1, acts as a DNA-binding transcriptional co-activator of laccase in Cryptococcus neoformans. Mol Microbiol 62:1090–1101CrossRefPubMedGoogle Scholar
  59. Zhu X, Williamson PR (2004) Role of laccase in the biology and virulence of Cryptococcus neoformans. FEMS Yeast Res 5:1–10CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Man-Shun Fu
    • 1
  • Rebecca A. Hall
    • 1
  • Fritz A. Mühlschlegel
    • 1
  1. 1.Department of BiosciencesUniversity of KentCanterburyUnited Kingdom

Personalised recommendations