Advertisement

Mycopathologia

, Volume 165, Issue 4–5, pp 249–258 | Cite as

Insights into the pathobiology of Paracoccidioides brasiliensis from transcriptome analysis—advances and perspectives

  • Simoneide S. Silva
  • Hugo C. Paes
  • Célia M. A. Soares
  • Larissa Fernandes
  • Maria Sueli S. Felipe
Article

Abstract

Paracoccidioiddes brasiliensis is a thermo-dimorphic fungus endemic to Latin America, where it causes the most prevalent systemic mycosis, paracoccidioidomycosis (PCM). DNA microarray technology has been used to identify patterns of gene expression when a microbe is confronted with conditions of interest, such as in vitro and/or ex vivo interaction with specific cells. P. brasiliensis is one organism that has benefited from this approach. Even though its genome has not been sequenced yet, much has been discovered from its transcriptome and DNA array analyses. In this review, we will outline the current knowledge in P.␣brasiliensis transcriptome, with focus on differential expression analysis in vitro and on the discussion of the genes that are controlled during the host–pathogen interaction ex vivo in order to give insights into the pathobiology of this fungus. In vitro experiments enabled the delineation of whole metabolic pathways; the description of differential metabolism between mycelium and yeast cells and of the mainly signaling pathways controlling dimorphism, high temperature growth, thermal and oxidative stress, and virulence/pathogenicity. Recent ex vivo experiments provided advances on the comprehension of the plasticity of response and indicate that P. brasiliensis is not only␣able to undergo fast and dramatic expression profile changes but can also discern subtle differences,␣such as whether it is being attacked by a macrophage or submitted to the bloodstream route conditions.

Keywords

Differential gene expression Host–pathogen interaction Macrophage response Paracoccidioides brasiliensis Transcriptome analysis 

Notes

Acknowledgments

This work was supported by FAP-DF/CNPq and MCT/CNPq and FUB. SSS, LF and HCP were supported by CNPq fellowship.

References

  1. 1.
    Restrepo A, Tobón A. Paracoccidioides brasiliensis. In: Mandell GL, Bennett JE, Dollin R, editors. Principles and␣practice of infectious diseases. Philadelphia; 2005. pp.␣3062–8.Google Scholar
  2. 2.
    Bagagli E, Bosco SMG, Theodoro RC, Franco M. Phylogenetic and evolutionary aspects of Paracoccidioides brasiliensis reveal a long coexistence with animal hosts that explains several biological features of the pathogen. Infect Genet Evol 2006;6:344–51.PubMedCrossRefGoogle Scholar
  3. 3.
    Cano MI, Cisalpino PS, Galindo I, Ramirez JL, Mortara RA, da Silveira JF. Electrophoretic karyotypes and genome sizing of the pathogenic fungus Paracoccidioides brasiliensis. J Clin Microbiol 1998;36:742–7.PubMedGoogle Scholar
  4. 4.
    Feitosa LS, Cisalpino PS, dos Santos MRM, Mortara RA, Barros TF, Morais FV, Puccia R, da Silveira JF, Camargo ZP. Chromosomal polymorphism, syntenic relationships, and ploidy in the pathogenic fungus Paracoccidioides brasiliensis. Fungal Genet Biol 2003;39:60–9.CrossRefGoogle Scholar
  5. 5.
    Almeida AJ, Matute DR, Carmona JA, Martins M, Torres I, McEwen JG, Restrepo A, Leão C, Ludovico P, Rodrigues F. Genome size and ploidy of Paracoccidioides brasiliensis reveals a haploid DNA content: flow cytometry and GP43 sequence analysis. Fungal Genet Biol 2007; 44:25–31.PubMedCrossRefGoogle Scholar
  6. 6.
    Villar LA, Salazar ME, Restrepo A. Morphological study of a variant of Paracoccidoides brasiliensis that exists in the yeast form at room temperature. J Med Vet Mycol 1988;26:269–76.PubMedCrossRefGoogle Scholar
  7. 7.
    McEwen JG, Restrepo BI, Salazar ME, Restrepo A. Nuclear staining of Paracoccidioides conidia. J Med Vet Mycol 1987;25:343–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Kurokawa CS, Lopes CR, Sugizaki MF, Kuramae EE, Franco MF, Peraçoli MTS. Virulence profile of ten Paracoccidioides brasiliensis isolates. Association with morphologic and genetic patterns. Rev Inst Med Trop Sao Paulo 2005;47:257–62.PubMedGoogle Scholar
  9. 9.
    Felipe MS, Andrade RV, Arraes FB, Nicola AM, Maranhao AQ, Torres FA, Silva-Pereira I, Pocas-Fonseca MJ, Campos EG, Moraes LM, Andrade PA, Tavares AH, Silva SS, Kyaw CM, Souza DP, Pereira M, Jesuino RS, Andrade EV, Parente JA, Oliveira GS, Barbosa MS, Martins NF, Fachin AL, Cardoso RS, Passos GA, Almeida NF, Walter ME, Soares CM, Carvalho MJ, Brigido MM. PbGenome network. Transcriptional profiles of the human pathogenic fungus Paracoccidioides brasiliensis in mycelium and yeast cells. J Biol Chem 2005;280:24706–14.PubMedCrossRefGoogle Scholar
  10. 10.
    Matute DR, McEwen JG, Puccia R, Montes BA, San-Blas G, Bagagli E, Rauscher JT, Restrepo A, Morais F, Nino-Veja G, Taylor JW. Cryptic speciation and recombination in the fungus Paracoccidioides brasileinsis as revealed by gene genealogies. Infect Genet Evol 2006;6:344–51.CrossRefGoogle Scholar
  11. 11.
    Soares CM, Madlun EE, da Silva SP, Pereira M, Felipe MS. Characterization of Paracoccidioides brasiliensis isolates by random amplified polymorphic DNA analysis. J␣Clin Microbiol 1995;33:505–7.PubMedGoogle Scholar
  12. 12.
    Matute DR, Sepulveda VE, Quesada LM, Goldman GH, Taylor JW, Restrepo A, McEwen JG. Microsatellite analysis of three phylogenetic species of Paracoccidioides brasiliensis. J Clin Microbiol 2006;44:2153–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Numata K, Kanai A, Saito R, Kondo S, Adachi J, Wilming LG, Hume DA, RIKEN GER Group GSL Members, Hayashizaki Y, Tomita M. Identification of putative noncoding RNAs among the RIKEN mouse full-length cDNA collection. Genome Res 2003;13:1301–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Nemecek JC, Wuthrich M, Klein BS. Global control of dimorphism and virulence in fungi. Science 2006;312: 583–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Agrawal N, Dasaradhi PVM, Mohmmed A, Malhotra P, Bhatnagar RK, Mukherjee SK. RNA interference, biology, mechanism, and applications. Microbiol Mol Biol Rev 2003;67:657–85.PubMedCrossRefGoogle Scholar
  16. 16.
    Nakayashiki H. RNA silencing in fungi: mechanisms and applications. FEBS Lett 2005;579:5950–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Galagan JE, Calvo SE, Cuomo C, Ma L, Wortman JR, Batzoglou S, Lee S, Bastürkmen M, Spevak CC, Clutterbuck J, Kapitonov V, Jurka J, Scazzocchio C, Farman M, Butler J, Purcell S, Harris S, Braus GH, Draht O, Busch S, D’Enfert C, Bouchier C, Goldman GH, Bell-Pedersen D, Griffiths-Jones S, Doonan JH, Yu J, Vienken K, Pain A, Freitag M, Selker EU, Archer DB, Peñalva MA, Oakley BR, Momany M, Tanaka T, Kumagai T, Asai K, Machida M, Nierman WC, Denning DW, Caddick M, Hynes M, Paoletti M, Fischer R, Miller B, Dyer P, Sach MS, Osmani SA, Birren BW. Sequencing of Aspergillus nidulans and comparative analysis with A. fumigatus and A. oryzae. Nature 2005;438:1105–15.PubMedCrossRefGoogle Scholar
  18. 18.
    Fan W, Kraus PR, Boily MJ, Heitman J. Cryptococcus neoformans gene expression during murine macrophage infection. Eukaryot Cell 2005;4:1420–33.PubMedCrossRefGoogle Scholar
  19. 19.
    Rasmussen TB, Skindersoe ME, Bjarnsholt T, Phipps RK, Christensen KB, Jensen PO, Andersen JB, Koch B, Larsen TO, Hentzer M, Eberl L, Hoiby N, Givskov M. Identity and effects of quorum-sensing inhibitors produced by Penicillium species. Microbiology 2005;151:1325–40.PubMedCrossRefGoogle Scholar
  20. 20.
    Felipe MS, Andrade RV, Petrofeza SS, Maranhao AQ, Torres FA, Albuquerque P, Arraes FB, Arruda M, Azevedo MO, Baptista AJ, Bataus LA, Borges CL, Campos EG, Cruz MR, Daher BS, Dantas A, Ferreira MA, Ghil GV, Jesuino RS, Kyaw CM, Leitao L,Martins CR, Moraes LM, Neves EO, Nicola AM, Alves ES, Parente JA, Pereira M,Pocas-Fonseca MJ, Resende R, Ribeiro BM, Saldanha RR, Santos SC, Silva-Pereira I, Silva MA, Silveira E, Simoes IC, Soares RB, Souza DP, De-Souza MT, Andrade EV, Xavier MA, Veiga HP, Venancio EJ, Carvalho MJ, Oliveira AG, Inoue MK, Almeida NF, Walter ME, Soares CM, Brigido MM. Transcriptome characterization of the␣dimorphic and pathogenic fungus Paracoccidioides brasiliensis by EST analysis. Yeast. 2003;20:263–71.PubMedCrossRefGoogle Scholar
  21. 21.
    Goldman GH, dos Reis Marques E, Duarte Ribeiro DC, de Souza Bernardes LA, Quiapin AC, Vitorelli PM, Savoldi M, Semighini CP, de Oliveira RC, Nunes LR, Travassos LR, Puccia R, Batista WL, Ferreira LE, Moreira JC, Bogossian AP, Tekaia F, Nobrega MP, Nobrega FG, Goldman MH. Expressed sequence tag analysis of the human pathogen Paracoccidioides brasiliensis yeast phase: identification of putative homologues of Candida albicans virulence and pathogenicity genes. Eukaryot Cell 2003;2:34–48.PubMedCrossRefGoogle Scholar
  22. 22.
    Nunes LR, Costa de Oliveira R, Leite DB, da Silva VS, dos Reis Marques E, da Silva Ferreira ME, Ribeiro DC, de Souza Bernardes LA, Goldman MH, Puccia R, Travassos LR, Batista WL, Nobrega MP, Nobrega FG, Yang DY, de Braganca Pereira CA, Goldman GH. Transcriptome analysis of Paracoccidioides brasiliensis cells undergoing mycelium-to-yeast transition Eukaryot Cell. 2005;l4: 2115–28.Google Scholar
  23. 23.
    Marques ER, Ferreira ME, Drummond RD, Felix JM, Menossi M, Savoldi M, Travassos LR, Puccia R, Batista WL, Carvalho KC, Goldman MH, Goldman GH. Identification of genes preferentially expressed in the pathogenic yeast phase of Paracoccidioides brasiliensis, using suppression subtraction hybridization and differential macroarray analysis. Mol Genet Genomics 2004;271: 667–77.PubMedCrossRefGoogle Scholar
  24. 24.
    Andrade RV, Paes HC, Nicola AM, de Carvalho MJ, Fachin AL, Cardoso RS, Silva SS, Fernandes L, Silva SP, Donadi EA, Sakamoto-Hojo ET, Passos GA, Soares CM, Brigido MM, Felipe MS. Cell organisation, sulphur metabolism and ion transport-related genes are differentially expressed in Paracoccidioides brasiliensis mycelium and yeast cells. BMC Genomics 2006;7:208.PubMedCrossRefGoogle Scholar
  25. 25.
    Rappleye CA, Eissenberg LG, Goldman WE. Histoplasma capsulatum alpha-(1,3)-glucan blocks innate immune recognition by the beta-glucan receptor. Proc Natl Acad Sci USA 2007;104:1366–70.PubMedCrossRefGoogle Scholar
  26. 26.
    Paris S, Duran-Gonzalez S, Mariat F. Nutritional studies on Paracoccidioides brasiliensis: the role of organic sulfur in dimorphism. Sabouraudia 1985;23:85–92.PubMedGoogle Scholar
  27. 27.
    Ferreira ME, Marques Edos R, Malavazi I, Torres I, Restrepo A, Nunes LR, de Oliveira RC, Goldman MH, Goldman GH. Transcriptome analysis and molecular studies on sulfur metabolism in the human pathogenic fungus Paracoccidioides brasiliensis. Mol Genet Genomics 2006;276:450–63.PubMedCrossRefGoogle Scholar
  28. 28.
    Bastos KP, Bailao AM, Borges CL, Faria FP, Felipe MS, Silva MG, Martins WS, Fiuza RB, Pereira M, Soares CM. The transcriptome analysis of early morphogenesis in Paracoccidioides brasiliensis mycelium reveals novel and induced genes potentially associated to the dimorphic process. BMC Microbiol 2007;7:29.PubMedCrossRefGoogle Scholar
  29. 29.
    Tavares AH, Silva SS, Bernardes VV, Maranhao AQ, Kyaw CM, Pocas-Fonseca M, Silva-Pereira I. Virulence insights from the Paracoccidioides brasiliensis transcriptome. Genet Mol Res 2005;4:372–89.PubMedGoogle Scholar
  30. 30.
    Tavares AH, Silva SS, Dantas A, Campos EG, Andrade RV, Maranhão AQ, Brígido MM, Passos-Silva DG, Facchin AL, Teixeira SM, Passos GA, Soares CM, Bocca AL, Carvalho MJ, Silva-Pereira I, Felipe MSS. Early transcriptional response of Paracoccidioides brasiliensis upon internalization by murine macrophages. Microbes Infect 2007;9:583–90.PubMedCrossRefGoogle Scholar
  31. 31.
    Bailão AM, Schrank A, Borges CL, Dutra V, Walquiria Ines Molinari-Madlum EE, Soares Felipe MS, Soares Mendes-Giannini MJ, Martins WS, Pereira M, Maria de Almeida Soares C. Differential gene expression by Paracoccidioides brasiliensis in host interaction conditions: representational difference analysis identifies candidate genes associated with fungal pathogenesis. Microbes Infect 2006;8:2686–97.PubMedCrossRefGoogle Scholar
  32. 32.
    Nau GJ, Richmond JFL, Schlesinger A, Jennings EG, Lander ES. Human macrophage activation programs induced by bacterial pathogens. Proc Natl Acad Sci USA 2000;99:1503–08.CrossRefGoogle Scholar
  33. 33.
    Dutra V, Nakazato L, Broetto L, Schrank IS, Vainstein MH, Schrank A. Application of representational difference analysis to identify sequence tags expressed by Metarhizium anisopliae during the infection process of the tick Boophilus microplus cuticle. Res Microbiol 2004;155: 245–51.PubMedCrossRefGoogle Scholar
  34. 34.
    Eskra L, Mathison A, Splitter R. Microarray analysis of mRNA levels from RAW264.7 macrophages infected with Brucella abortus. Infect Immun 2003;71:1125–33.PubMedCrossRefGoogle Scholar
  35. 35.
    Kim HS, Choi EH, Khan J, Roilides E, Francesconi A, Kasai M, Sein T, Schaufele RL, Sakurai K, Son CG, Greer BT, Chanock S, Lyman CA, Walsh TJ. Expression of genes encoding innate host defense molecules in normal human monocytes in response to Candida albicans. Infect Immun 2005;73:3714–24.PubMedCrossRefGoogle Scholar
  36. 36.
    Cortez KJ, Lyman CA, Kottilil S, Kim HS, Roilides E, Yang J, Fullmer B, Lempicki R, Walsh TJ. Functional genomics of innate host defense molecules en normal human monocytes in response to Aspergillus fumigatus. Infect Immun 2006;74:2353–65.PubMedCrossRefGoogle Scholar
  37. 37.
    Brummer E, Hanson LH, Restrepo A, Stevens DA. Intracellular multiplication of Paracoccidioides brasiliensis in macrophages: killing and restriction of multiplication by activated macrophages. Infect Immun 1989;57:2289–94.PubMedGoogle Scholar
  38. 38.
    Lorenz MC, Bender JA, Fink GR. Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot Cell 2004;3:1076–87.PubMedCrossRefGoogle Scholar
  39. 39.
    Chatterjee SS, Hossain H, Otten S, Kuenne C, Kuchmina K, Machata S, Domann E, Chakraborty T, Hain T. Intracellular gene expression profile of Listeria monocytogenes. Infect Immun 2006;74:1323–38.PubMedCrossRefGoogle Scholar
  40. 40.
    Franco M, Peracoli MT, Soares A, Montenegro R, Mendes RP, Meira DA. Host–parasite relationship in paracoccidioidomycosis. Curr Top Med Mycol 1993;5:115–49.PubMedGoogle Scholar
  41. 41.
    Fradin C, Kretschmar Nichterlein T, Gaillardin C, d’Enfert C, Hube B. Stage-specific gene expression of Candida albicans in human blood. Mol Microbiol 2003;47:1523–43.PubMedCrossRefGoogle Scholar
  42. 42.
    Castro NS, Maia ZA, Pereira M, Soares CM. Screening for glycosylphosphatidylinositol-anchored proteins in the Paracoccidioides brasiliensis transcriptome. Genet Mol Res 2005;4:326–345.Google Scholar
  43. 43.
    Martchenko MA, Alarco M, Harcus D, Whiteway M. Superoxide dismutases in Candida albicans: transcriptional regulation and functional characterization of the␣hyphal-induced SOD5 gene. Mol Biol Cell 2004;15: 456–67.PubMedCrossRefGoogle Scholar
  44. 44.
    San-Blas G, San-Blas F. Paracoccidioides brasiliensis: cell wall structure and virulence—a review. Mycopathologia 1977;62:77–86.PubMedCrossRefGoogle Scholar
  45. 45.
    Klimpel KR, Goldman WE. Cell walls from avirulent variants of Histoplasma capsulatum lack alpha-(1,3)-glucan. Infect Immun 1988;56:2997–3000.PubMedGoogle Scholar
  46. 46.
    Calvi SA, Peracoli MT, Mendes RP, Marcondes-Machado J, Fecchio D, Marques SA, Soares AM. Effect of cytokines on the in vitro fungicidal activity of monocytes from paracoccidioidomycosis patients. Microbes Infect 2003;5: 107–13.PubMedCrossRefGoogle Scholar
  47. 47.
    Souto JT, Figueiredo F, Furlanetto A, Pfeffer K, Rossi MA, Silva JS. Interferongamma and tumor necrosis factor-alpha determine resistance to Paracoccidioides brasiliensis infection in mice. Am J Pathol 2000;156:1811–20.PubMedGoogle Scholar
  48. 48.
    Ram AF, Arentshorst M, Damueld RA, Vankuyk PA, Klis FM, van den Hondel CAMJJ. The cell wall stress response in Aspergillus niger involves increased expression of the glutamine: fructose-6-phosphate amidotransferase-encoding gene (gfaA) and increased deposition of chitin in the cell wall. Microbiology 2004;15:3315–26.CrossRefGoogle Scholar
  49. 49.
    Roman E, Nombela C, Pla J. The sho1 adaptor protein links oxidative stress to morphogenesis and cell wall biosynthesis in the fungal pathogen Candida albicans. Mol Cell Biol Rev 2005;25:10611–27.CrossRefGoogle Scholar
  50. 50.
    Boldrick JC, Alizadeh AA, Diehn M, Dudoit S, Liu CL, Belcher CE, Botstein D, Staudt LM, Brown PO, Relman DA. Stereotyped and specific gene expression programs in human innate immune responses to bacteria. Proc Natl Acad Sci USA 2002;99:972–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Wang JP, Rought SE, Jacques C, Guiney DG. Gene expression profiling detects patterns of human macrophage responses following Mycobacterium tuberculosis infection. FEMS Immun Med Microb 2003;39:163–72.CrossRefGoogle Scholar
  52. 52.
    Silva SS, Tavares AH, Passos-Silva DG, Facchin AL, Teixeira SM, Soares CM, Bocca AL, Carvalho MJ, Silva-Pereira I, Passos GA, Felipe MS. Transcriptional response of murine macrophages upon infection with opsonized Paracoccidioides brasiliensis. Microbes Infect 2007; MICINF-D-07–00160R1.Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  • Simoneide S. Silva
    • 1
  • Hugo C. Paes
    • 1
  • Célia M. A. Soares
    • 2
  • Larissa Fernandes
    • 1
  • Maria Sueli S. Felipe
    • 1
  1. 1.Laboratório de Biologia Molecular, Departamento de Biologia CelularUniversidade de BrasíliaBrasiliaBrazil
  2. 2.Departamento de Bioquímica e Biologia MolecularUniversidade Federal de GoiásGoianiaBrazil

Personalised recommendations