Melanin as a virulence factor of Paracoccidioides brasiliensis and other dimorphic pathogenic fungi: a minireview

1. Piattelli M, Fattorusso E, Nicolaus RA, Magno S. The structure of melanins and melanogenesis. V Ustilago melanin Tetrahedron 1965;21:3229–36.

   Article  CAS  Google Scholar 

2. Hamilton AJ, Gomez BL. Melanins in fungal pathogens. J␣Med Microbiol 2002;51:189–91.

   PubMed  CAS  Google Scholar 

3. Sanchez-Ferrer A, Rodrigues-Lopez JN, Garcia-Canova F, Garcia-Carmona F. Tyrosinase: a comprehensive review of its mechanism. Biochem Biophys Acta 1995;1247:1–11.

   PubMed  Google Scholar 

4. Wheelr MH, Bell AA. Melanins and their importance in pathogenic fungi. Curr Top Med Mycol 1988;2:338–87.

   Google Scholar 

5. Romero-Martinez R, Wheeler M, Guerrero-Plata A, Rico G, Torres-Guerrero H. Biosynthesis and functions of melanin in Sporothrix schenckii. Infect Immun 2000;68: 3696–703.

   Article  PubMed  CAS  Google Scholar 

6. Wheeler MH. Comparisons of fungal melanin biosynthesis in ascomycetous, imperfect and basidiomycetous fungi. Trans Br Mycol Soc 1983;81:29–36.

   Article  CAS  Google Scholar 

7. Taylor B, Wheeler MH, Szaniszlo PJ. Evidence for pentaketide melanin biosynthesis in dematiaceous human pathogenic fungi. Mycologia 1987;79:320–2.

   Article  CAS  Google Scholar 

8. Alviano CS, Farbiarz SR, De Souza W, Angluster J, Travassos LR. Characterization of Fonsecaea pedrosoi melanin. J Gen Microbiol 1991;137:837–44.

   PubMed  CAS  Google Scholar 

9. Youngchim S, Morris-Jones R, Hay RJ, Hamilton AJ. Production of melanin by Aspergillus fumigatus. J Med Microbiol 2004;53:175–81.

   Article  PubMed  CAS  Google Scholar 

10. Bell AA, Wheeler MH. Biosynthesis and functions of fungal melanins. Annu Rev Phytopathol 1986;24:411–51.

    Article  CAS  Google Scholar 

11. Kwon-Chung KJ, Tom WK, Costa JL. Utilization of indole compounds by Cryptococcus neoformans to produce a melanin-like pigment. J Clin Microbiol 1983;18:1419–21.

    PubMed  CAS  Google Scholar 

12. Staib F. Cryptococcus neoformans and Guizotia abyssicnica (syn. G. Oleifera D.C.). Z Hyg 1962;148:466–75.

    Article  Google Scholar 

13. Wang Y, Casadevall A. Melanin, melanin “ghosts”, and melanin composition in Cryptococcus neoformans. Infect Immun 1996;64:2420–4.

    PubMed  CAS  Google Scholar 

14. Da Silva MB, Marques AF, Nosanchuk JD, Casadevall A, Travassos LR, Taborda CP. Melanin in the dimorphic fungal pathogen Paracoccidioides brasiliensis: effects on phagocytosis, intracellular resistance and drug susceptibility. Microbes Infect 2006;8:197–205.

    Article  PubMed  CAS  Google Scholar 

15. Gómez BL, Nosanchuk JD, Díez S, YoungchimS, Aisen P, Cano LE, Restrepo A, Casadevall A, Hamilton AJ. Detection of melanin-like particles in the dimorphic fungal pathogen Paracoccidioides brasiliensis in vitro and during infection. Infect Immun 2001;69:5760–7.

    Article  PubMed  Google Scholar 

16. Nosanchuk JD, Gomez BL, Youngchim S, Diez S, Aisen P, Zancope-Oliveira RM, Restrepo A, Casadevall A, Hamilton AJ. Histoplasma capsulatum synthesizes melanin-Like pigments in vitro and during mammalian infection. Infect Immun 2002;70:5124–31.

    Article  PubMed  CAS  Google Scholar 

17. Nosanchuk JD, van Duin D, Mandal P, Aisen P, Legendre AM, Casadevall A. Blastomyces dermatitidis produces melanin in vitro and during infection. FEMS Microbiol Lett 2004;239(1):187–93.

    Article  PubMed  CAS  Google Scholar 

18. Morris-Jones R, Gomez BL, Diez S, Uran M, Morris-Jones SD, Casadevall A, Nosanchuk JD, Hamilton AJ. Synthesis of melanin pigment by Candida albicans in vitro and during infection. Infect Immun 2005;73(9):6147–50.

    Article  PubMed  CAS  Google Scholar 

19. Nosanchuk JD, Yu JJ, Hung CY, Casadevall A, Cole GT. Coccidioides posadasii produces melanin in vitro and during infection. Fungal Genet Biol 2007;44:517–20.

    Article  PubMed  CAS  Google Scholar 

20. Rosas AL, Nosanchuk JD, FeldmesserM, Cox GM, McDade HC, Casadevall A. Synthesis of polymerized melanin by Cryptococcus neoformans in infected rodents. Infect Immun 2000;68:2845–53.

    Article  PubMed  CAS  Google Scholar 

21. Eisenman HC, Nosanchuk JD, Webber JB, Emerson RJ, Camesano TA, Casadevall A. Microstructure of cell wall-associated melanin in the human pathogenic fungus Cryptococcus neoformans. Biochemistry 2005;44(10): 3683–93.

    Article  PubMed  CAS  Google Scholar 

22. Jacobson ES, Ikeda R. Effect of melanization upon porosity of the cryptococcal cell wall. Med Mycol 2005;43: 327–33.

    Article  PubMed  CAS  Google Scholar 

23. Steenbergen JN, Casadevall A. The origin and maintenance of virulence for the human pathogenic fungus Cryptococcus neoformans. Microbes Infect 2003;5:667–75.

    Article  PubMed  Google Scholar 

24. Nosanchuk JD, Casadevall A. Impact of melanin on microbial virulence and clinical resistance to antimicrobial compounds. Antimicrob Agents Chemother 2006;50:3519–28.

    Article  PubMed  CAS  Google Scholar 

25. Steenbergen JN, Shuman HA, Casadevall A. Cryptococcus neoformans interactions with amoebae suggest an explanation for its virulence and intracellular pathogenic strategy in macrophage. Proc Natl Acad Sci USA 2001;98: 15245–50.

    Article  PubMed  CAS  Google Scholar 

26. Mylonakis E, Ausubel FM, Perfect JR, Heitman J, Calderwood SB. Killing of Caenorhabditis elegans by Cryptococcus neoformans as a model of yeast pathogenesis. Proc Natl Acad Sci USA 2002;99:15675–80.

    Article  PubMed  CAS  Google Scholar 

27. Rosas AL, Casadevall A. Melanization decrease the susceptibility of Cryptococcus neoformans to enzymatic degradation. Mycopathologia 2001;151:53–6.

    Article  PubMed  CAS  Google Scholar 

28. Nosanchuk JD, Casadevall A. The contribution of melanin to microbial pathogenesis. Cell Microbiol 2003;5:203–23.

    Article  PubMed  CAS  Google Scholar 

29. Mironenko NV, Alekhina IA, Zhdanova NN, Bulat SA. Intraspecific variation in gamma-radiation resistance and genomic structure in the filamentous fungus Alternaria alternata: a case study of strains inhabiting Chernobyl reactor No. 4. Ecotoxicol Environ Saf 2000;45:177–87.

    Article  PubMed  CAS  Google Scholar 

30. Rosas AL, Casadevall A. Melanization affects susceptibility of Cryptococcus neoformans to heat and cold. FEMS Microbiol Lett 1997;153:265–72.

    PubMed  CAS  Google Scholar 

31. Nosanchuk JD, Rosas AL, Casadevall A. Antibody response to fungal melanin in mice. J Immunol 1998;160: 6026–31.

    PubMed  CAS  Google Scholar 

32. Mohagheghpour N, Waleh N, Garger SJ, Dousman L, Grill LK, Tuse D. Synthetic melanin suppresses production of proinflammatory cytokines. Cell Immunol 2000;199:25–36.

    Article  PubMed  CAS  Google Scholar 

33. Huffnagle GB, Chen GH, Curtis JL, McDonald RA, Strieter RM, Tower GB. Down-regulation of the afferent phase of T cell-mediated pulmonary inflammation and immunity by a high melanin-producing strain of Cryptococcus neoformans. J Immunol 1995;155:3507–16.

    PubMed  CAS  Google Scholar 

34. Mednick AJ, Nosanchuk JD, Casadevall A. Melanization of Cryptococcus neoformans affects lung inflammatory responses during cryptococcal infection. Infect Immun 2005;73:2012–9.

    Article  PubMed  CAS  Google Scholar 

35. Restrepo A. The ecology of Paracoccidioides brasiliensis: a puzzle still unsolved. Sabouraudia 1985;23(5):323–34 (Review).

    Google Scholar 

36. McEwen JG, Garcia AM, Ortiz BL, Botero S, Restrepo A. In search of the natural habitat of Paracoccidioides brasiliensis. Arch Med Res 1995;26:305–6.

    PubMed  CAS  Google Scholar 

37. Marques-da-Silva SH, Colombo AL, Blotta MH, Queiroz-Telles F, Balthazar AB, Lopes JD, Camargo ZP. Diagnosis paracoccidioidomycosis by detection of antigen and antibody in bronchoalveolar lavage fluids. Clin Vaccine Immunol 2006;13:1363–6.

    Article  PubMed  CAS  Google Scholar 

38. Coutinho ZF, Silva D, Lazera M, Petri V, Oliveira RM, Sabroza PC, Wanke B. Paracoccidioidomycosis mortality in Brazil (1980–1995). Cad Saude Publica 2002;18(5): 1441–54.

    PubMed  Google Scholar 

39. Franco M, Peracoli MT, Soares A, Montenegro R, Mendes RP, Meira DA. Host–parasite relationship in paracoccidioidomycosis. Curr Top Med Mycol 1993;5:115–149 (Review).

    Google Scholar 

40. Wang Y, Aisen P, Casadevall A. Cryptococcus neoformans melanin and virulence: mechanism of action. Infect Immun 1995;63:3131–6.

    PubMed  CAS  Google Scholar 

41. White LP. Melanin: a naturally occurring cation exchange material. Nature 1958;182:1427–8.

    Article  PubMed  CAS  Google Scholar 

42. Nosanchuk J, Casadevall A. Cellular charge of Cryptococcus neoformans: contributions from the capsular polysaccharide, melanin, and monoclonal antibody binding. Infect Immun 1997;65:1836–41.

    PubMed  CAS  Google Scholar 

43. Rosas AL, Nosanchuk JD, Casadevall A. Passive immunization with melanin-binding monoclonal antibodies prolong survival of mice with lethal Cryptococcus neoformans infection. Infect Immun 2001;69:3410–2.

    Article  PubMed  CAS  Google Scholar 

44. Da Silva MB, Marques AF, Svidzinski A, Nosanchuk, JD, Casadevall A, Travassos LR, Taborda CP. Protective role of Melanin in Paracoccidioides brasiliensis against yeast cells phagocytosis and susceptibility to antimicrobial oxidants (Data not published).

45. Wang Y, Aisen P, Casadevall A. Melanin, melanin “ghosts,” and melanin composition in Cryptococcus neoformans. Infect Immun 1996;64(7):2420–4.

    PubMed  CAS  Google Scholar 

46. Cunha MM, Franzen AJ, Alviano DS, Zanardi E, Alviano CS, De Souza W, Rozental S. Inhibition of melanin synthesis pathway by tricyclazole increases susceptibility of Fonsecaea pedrosoi against mouse macrophages. Microsc Res Tech 2005;68(6):377–84.

    Article  PubMed  CAS  Google Scholar 

47. Peltroche-Llacsahuanga H, Schnitzler N, Jentsch S, Platz A, De Hoog S, Schweizer KG, Haase G. Analyses of phagocytosis, evoked oxidative burst, and killing of black yeasts by human neutrophils: a tool for estimating their pathogenicity? Med Mycol 2003;41(1):7–14.

    Article  PubMed  CAS  Google Scholar 

48. Sichel G, Corsaro C, Scalia M, Di Bilio AJ, Bonomo RP. In vitro scavenger activity of some flavonoids and melanins against O2−(.). Free Radic Biol Med 1991;11(1):1–8.

    Article  PubMed  CAS  Google Scholar 

49. Gan EV, Lam KM, Haberman HF, Menon IA. Oxidizing and reducing properties of melanins. Br J Dermatol 1977;96(1):25–8.

    Article  PubMed  CAS  Google Scholar 

50. Ikeda R, Sugita T, Jacobson ES, Shinoda T. Effects of melanin upon susceptibility of Cryptococcus neoformans to antifungals. Microbiol Immunol 2003;47:271–7.

    PubMed  CAS  Google Scholar 

51. Van Duin D, Casadevall A, Nosanchuk JD. Melanization of Cryptococcus neoformans and Histoplasma capsulatum reduces their susceptibility to amphotericin B and caspofungin. Antimicrob Agents Chemother 2002;34:3394–400.

    Article  CAS  Google Scholar 

52. Rhodes JC, Polacheck I, Kwon-Chung KJ. Phenoloxidase activity and virulence in isogenic strains of Cryptococcus neoformans. Infect Immun 1982;36(3):1175–84.

    PubMed  CAS  Google Scholar 

53. Waterman SR, Hacham M, Panepinto J, Hu G, Shin S, Williamson PR. Cell wall targeting of laccase of Cryptococcus neoformans during infection of mice. Infect Immun 2007;75:714–22.

    Article  PubMed  CAS  Google Scholar 

54. Zhu X, Gibbons J, Garcia-Rivera J, Casadevall A, Williamson PR. Laccase of Cryptococcus neoformans is a cell wall-associated virulence factor. Infect Immun 2001;69(9): 5589–96.

    Article  PubMed  CAS  Google Scholar 

55. Tse DC, McCreery RL, Adams RN. Potential oxidative pathways of brain catecholamines. J Med Chem 1976;19 (1):37–40.

    Article  PubMed  CAS  Google Scholar 

56. Liu L, Tewari RP, Williamson PR. Laccase protects Cryptococcus neoformans from antifungal activity of alveolar macrophages. Infect Immun 1999;67:6034–9.

    PubMed  CAS  Google Scholar 

57. Zhu X, Williamson PR. Role of laccase in the biology and virulence of Cryptococcus neoformans. FEMS Yeast Res 2004;5(1):1–10.

    Article  PubMed  CAS  Google Scholar 

58. Mariat F. Observations sur l’ecologie de Sporothrix schenckii et de Ceraticystis stenoceras en Corse et en Alsace, provinces françaises indemnes de sporothicose. Sabouraudia 1975;13:217–25.

    PubMed  CAS  Google Scholar 

59. Davis BA. Sporotrichosis. Dermatol Clin 1996;14:69–76.

    Article  PubMed  CAS  Google Scholar 

60. Mendonça-Previato L, Gorin PAJ, Travassos LR. Galactose-containing polysaccharides from the human pathogens Sporothrix schenckii and Ceratocystis stenoceras. Infect Immun 1980;29:934–9.

    PubMed  Google Scholar 

61. Durden FM, Elewski B. Fungal infections in HIV patients. Semin Cutan Med Surg 1997;16:200–12.

    Article  PubMed  CAS  Google Scholar 

62. Morris-Jones R, Youngchim S, Gomez BL, Aisen P, Hay RJ, Nosanchuk JD, Casadevall A, Hamilton AJ. Synthesis of melanin-like pigments by Sporothrix schenckii in vitro and during mammalian infection. Infect Immun 2003;71: 4026–33.

    Article  PubMed  CAS  Google Scholar 

63. Kauffman CA. Histoplasmose: a clinical and laboratory update. Clin Microbiol Rev 2007;20:115–32.

    Article  PubMed  CAS  Google Scholar 

64. Graybill JR. Histoplasmosis and AIDS. J Infect Dis 1988;158:623–6.

    PubMed  CAS  Google Scholar 

65. Wheat J. Histoplasmosis in the acquired immunodeficiency syndrome. Curr Top Med Mycol 1996;7:7–18.

    PubMed  CAS  Google Scholar 

66. Bradsher RW, Chapman SW, Pappas PG. Blastomycosis. Infect Dis Clin North Am 2003;17:21–40, vii.

67. Pappas PG, Threlkeld MG, Bedsole GD, Cleveland KO, Gelfand MS, Dismukes WE. Blastomycosis in immunocompromised patients. Medicine (Baltimore) 1993;72: 311–25.

    CAS  Google Scholar 

68. Fisher MC, Koenig GL, White TJ, Taylor JW. Molecular and phenotypic description of Coccidioides posadasii sp nov., previously recognized as the non-California population of Coccidioides immitis. Mycologia 2002;94:73–84.

    Article  CAS  Google Scholar 

69. Cole GT, Xue JM, Okeke CN, Tarcha EJ, Basrur V, Schaller RA, Herr RA, Yu JJ, Hung CY. A vaccine against coccidiodomycosis is justified and attainable. Med Mycol 2004;42:189–216.

    Article  PubMed  CAS  Google Scholar 

70. Nosanchuk JD, Ovalle R, Casadevall A. Glyphosate inhibits melanization of Cryptococcus neoformans and prolongs survival of mice after systemic infection. J Infect Dis 2001;183:1093–9.

    Article  PubMed  CAS  Google Scholar 

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