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A common term in the description of pathogens is virulence factor. A fungal infection is generally an accidental encounter in the life cycle of the fungus. It is likely that there are many subtle virulence factors in fungi, such as the simple ability to survive and grow within the host, that are important to their ability to be pathogens. The focus on Cryptococcus neoformans and its melanin production has two potential benefits. First, it may help to understand the regulation of virulence of this infection with a well-defined phenotype that is easy to measure. Second, with further understanding of the molecular biology and biochemistry of melanin, it could become a unique and selective target for antifungal drugs against C. neoformans and other dematiaceous fungi. Identification and characterization of extracellular proteins in C. neoformans are important because proteinases, esterases, and lipases have been associated with virulence in other pathogens, and these proteins may also elicit strong immune responses from the host. The potential importance of urease in the virulence composite could involve its ability to change local pH in the host, such as when the yeast resides in a phagolysosome. Production of the phospholipases appears to be extracellular, and at least one enzymatic component appears to be phospholipase B.
1. Alspaugh, J. A.,, J. R. Perfect,, and J. Heitman. 1997. Cryptococcus neoformans mating and virulence are regulated by the G-protein alpha subunit GPA1 and cAMP. Genes Dev. 11: 3206– 3217.
2. Aoki, S.,, S. Ito-kowa,, K. Nakamura,, J. Kato,, K. Ninomiya,, and V. Vidotto. 1994. Extracellular proteolytic activity of Cryptococcus neoformans. Mycopathologia 128: 143– 150.
3. Bava, A. J.,, R. Negroni,, and M. Bianchi. 1993. Cryptococcosis produced by a urease negative strain of Cryptococcus neoformans. J. Med. Vet. Mycol. 31: 87– 89.
4. Boekhout, T.,, and G. Scorzetti. 1997. Differential killer toxin sensitivity patterns of varieties of Cryptococcus neoformans. J. Med. Vet. Mycol. 35: 147– 149.
5. Bottone, E. J.,, B. E. Johnasson,, M. Toma,, and G. P. Wormser. 1986. Poorly encapsulated Cryptococcus neoformans from patients with AIDS. I. Preliminary observations. AIDS Res. Hum. Retroviruses 2: 221.
6. Bottone, E. J.,, M. Toma,, B. E. Johansson,, and G. P. Wormser. 1985. Capsule-deficient Cryptococcus neoformans in AIDS patients. Lancet ii: 553.
7. Brueske, C. H. 1986. Proteolytic activity of a clinical isolate of Cryptococcus neoformans. J. Clin. Microbiol. 23: 631.
8. Bulmer G. S.,, and J. R. Tacken 1975. Phagocytosis of Cryptococcus neoformans by alveolar macrophages. Infect. Immun. 11: 73– 79.
9. Canteros, C.,, C. Rivas,, L. Rodero,, and G. Davel. 1996. Quantitative urease detection of clinical and environmental strains of Cryptococcus neoformans, abstr. 1.5:150. 3rd International Conference on Cryptococcus and Cryptococcosis, Paris.
10. Chang, Y. C.,, R. Cherniak,, T. R. Kozel,, D. L. Granger,, L. C. Morris,, L. C. Weinhold,, and K. J. Kwon-Chung. 1997. Structure and biological activities of acapsular Cryptococcus neoformans 602 complemented with CAP64 gene. Infect. Immun. 65: 1584– 1592.
11. Chang, Y. C.,, and K. J. Kwon-Chung. 1994. Complementation of a capsule-deficiency mutation of Cryptococcus neoformans restores its virulence. Mol. Cell. Biol. 14: 4912– 4919.
12. Chang, Y.C.,, and K. J. Kwon-Chung. Molecular dissection of capsule formation in Cryptococcus neoformans, abstr 7.2: 132– 133. 3rd International Conference on Cryptococcus and Cryptococcosis, Paris.
13. 12a. Chang, Y. C.,, and K. J. Kwon-Chung. 1998. Isolation of the third capsule-associated gene, CAP60, required for virulence in Cryptococcus neoformans. Infect. Immun. 66: 2230– 2236.
13. Chang, Y. C.,, L. A. Penoyer,, and K. J. Kwon-Chung. 1996. The second capsule gene of Cryptococcus neoformans, Cap64, is essential for virulence. Infect. Immun. 64: 1977– 1983.
14. Chaturvedi, V.,, A. Bartiss,, and B. Wong. 1997. Induced expression of bacterial mtlD supplements mannitol production in a mannitol mutant of Cryptococcus neoformans, abstr. 019:81. 13th Congress of International Society for Human and Animal Mycology, Italy.
15. Chaturvedi, V. P.,, T. Flynn,, W. G. Niehaus,, and B. Wong. 1996. Stress tolerance and pathogenic potential of a mannitol-mutant of Cryptococcus neoformans. Microbiology 142: 937– 943.
16. Chaturvedi, V. P.,, B. Wong,, and S. L. Newman. 1996. Oxidative killing of Cryptococcus neoformans by human neutrophils: evidence that fungal mannitol protects by scavengering reactive oxygen intermediates. J. Immunol 156: 3836– 3840.
17. Chen, L. G.,, E. S. Blank,, and A. Casadevall. 1996. Extracellular proteinase activity of Cryptococcus neoformans. Clin. Diagn. Lab. Immunol. 3: 570– 574.
18. Chen, L. G.,, L. A. Pirofski,, and A. Casadevall. 1997. Extracellular proteins of Cryptococcus neoformans and host antibody response. Infect. Immun. 65: 2599– 2605.
19. Chen, S.G.,, L. G. Wright,, R. T. Santangelo,, M. Muller,, V. R. Moran,, P. W. Kuchel,, and T. C. Sorrell. 1997. Identification of extracellular phospholipase B, lysophospholipase, acyltransferase produced by Cryptococcus neoformans. Infect. Immun. 65: 405– 411.
20. Chen, S. C. A.,, M. Muller,, J. Z. Zhou,, L. G Wright,, and T. C. Sorrell. 1997. Phospholipase activity in Cryptococcus neoformans: a new virulence factor? J. Infect. Dis. 175: 414– 420.
21. Chemiak, R.L.,, L. GMorris,, T. Belay,, E. D. Spitzer,, and A. Casadevall. 1995. Variation in thestructure of gluoironoxylomannan in isolates from patients with recurrent cryptococcal meningitis. Infect. Immun. 63: 1899– 1905.
22. Collins, H. L.,, and G. J. Bancroft. 1991. Encapsulation of Cryptococcus neoformans impairs antigen-specific T-cell responses. Infect. Immun. 59: 3883– 3888.
23. Courchesne, W.,, C. Savoy,, and D. M. Lupan. 1996. Mutants of C. neoformans defective in mating and virulence, abstr 1.8:151. 3rd International Conference on Cryptococcus and Cryptococcosis, Paris.
26. 23a. Cox, G. M., et al. Unpublished data.
24. Cox, G. M.,, G. T. Cole,, and J. R. Perfect. 1996. Identification and disruption of the Cryptococcus neoformans urease gene, abstr. 1.6:150. 3rd International Conference on Cryptococcus and Cryptococcosis, Paris.
25. Curtis, J. L.,, G. B. Huffnagle,, G.-H. Chen,, M. L. Warnock,, M. R. Gyetko,, R. A. McDonald,, P. J. Scott,, and G. B. Toews. 1994. Experimental murine pulmonary cryptococcosis: differences in pulmonary inflammation and lymphocyte recruitment induced by two encapsulated strains of Cryptococcus neoformans. Lab. Invest. 71: 113– 126.
26. Cutler, J. E. 1991. Putative virulence factors of Candida albicans. Annu. Rev. Microbiol. 45: 187– 218.
27. Denning, D. W.,, R. W. Armstrong,, B. H. Lewis,, and D. A. Stevens. 1991. Elevated cerebrospinal fluid pressures in patients with cryptococcal meningitis and acquired immunodeficiency syndrome. Am. J. Med. 91: 267– 272.
28. Dixon, D. M.,, and A. Polak. 1986. In vivo and in vitro studies with an atypical, rhinotrophic isolate of Cryptococcus neoformans. Mycopathologia 96: 33– 40.
29. Dixon, D. M.,, A. Polak,, and P. J. Szaniszlo. 1987. Pathogenicity and virulence of wild-type and melanin-deficient Wangiella dermatitidis. J. Med. Vet. Mycol. 25: 97– 106.
30. Dong, Z. M.,, and J. W. Murphy. 1995. Effects of the two varieties of Cryptococcus neoformans cells and culture filtrate antigens on neutrophil locomotion. Infect. Immun. 63: 2632– 2644.
31. Dong, Z. M.,, and J. W. Murphy. 1996. Cryptococcal polysaccharides induce L-selectin shedding and tumor necrosis factor receptor loss from the surface of human neutrophils. J. Clin. Invest. 97: 689– 698.
32. Drouhet, E.,, and G. Segretain. 1951. Inhibition de la migration leucocytaire in vitro par un polyoside capsulaire de Torulopsis (Cryptococcus) neoformans. Ann. Inst. Pasteur 81: 674.
33. Duguid, J. R.,, R. G. Rohwer,, and B. Seed. 1988. Isolation of cDNA of scrapie-modu-lated RNAs by substractive hybridization of cDNA library. Proc. Natl. Acad. Sci. USA 85: 5738– 5742.
34. Dykstra, M. A.,, L. Friedman,, and J. W. Murphy. 1977. Capsule size of Cryptococcus neoformans: control and relationship to virulence. Infect. Immun. 16: 129.
35. Edman, J. C. 1992. Isolation of telomerelike sequences from Cryptococcus neoformans and their use in high-frequency transformation. Mol. Cell. Biol. 12: 2777– 2783.
36. Edman, J.C. 1996. P aradoxes of mating in Cryptococcus neoformans, abstr. 1.1:7. 3rdInternational Conference on Cryptococcus and Cryptococcosis, Paris.
37. Edman, J. C.,, and K. J. Kwon-Chung. 1990. Isolation of the URA5 gene from Cryptococcus neoformans var. neoformans and its use as a selective marker for transformation. Mol. Cell. Biol. 10: 4538– 4544.
38. Falkow, S. 1988. Molecular Koch's postulates applied to microbial pathogenicity. Rev. Infect. Dis. 10( Suppl. 2): 5274r– 5276.
39. Farmer, S. G.,, and R. A. Komorowski. 1973. Histologic response to capsule-deficient Cryptococcus neoformans. Arch. Pathol. 96: 383– 387.
40. Firestine, S. M.,, S. Misialek,, D. Toffaletti,, T. J. Klem,, J. R. Perfect,, and V. J. Davisson. 1998. Biochemical role of the Cryptococcus neoformans ADE2 protein in fungal de novo purine biosynthesis. Arch. Biochem. Biophys. 351: 123– 134.
41. Franzot, S. P.,, J. Mukherjee,, R. Cherniak,, L. Chen,, J. S. Hamdan,, and A. Casadevall. 1998. Microevolution of a standard strain of Cryptococcus neoformans resulting in differences in virulence and other phenotypes. Infect. Immun. 66: 89– 97.
42. Fromtling, R. A.,, G. K. Abruzzo,, and A. Ruiz. 1988. Cryptococcus neoformans: a central nervous system isolate from an AIDS patient that is rhinotropic in a normal mouse model. Mycopathologia 102: 72– 86.
43. Fromtling, R. A.,, G. K. Abruzzo,, and A. Ruiz. 1989. Virulence and antifungal susceptibility of environmental and clinical isolates of Cryptococcus neoformans from Puerto Rico. Mycopathologia 106: 163– 166.
44. Fromtling, R. A.,, H. J. Shadomy,, and E. S. Jacobson. 1982. Decreased virulence in stable, acapsular mutants of Cryptococcus neoformans. Mycopathologia 79: 23– 29.
45. Gabriel, D. W. 1986. Specificity and gene function in plant-pathogen interactions. ASM News 52: 19– 25.
46. Galgiani, J. N. 1996. Identification and cloning of a 20KDA protein from Cryptococcus neoformans that stimulates murine delayed-type hypersensitivity, abstr. 17. 3rd International Conference on Cryptococcus and Cryptococcosis, Paris.
47. Gao, S.,, and D. L. Nuss. 1996. Distinct roles for two G-protein alpha subunits in fungal virulence, morphology and reproduction revealed by targeted gene disruption. Proc. Natl. Acad. Sci. USA 93: 14122– 14127.
48. Goldman, D.,, S. C. Lee,, and A. Casadevall. 1994. Pathogenesis of pulmonary Cryptococcus neoformans infection in the rat. Infect. Immun. 62: 4755– 4761.
49. Gottfredsson, M.,, G. M. Cox,, M. Ghannoum,, and J. R. Perfect. 1998. Molecular cloning of the Cryptococcus neoformans phospholipase B gene, a putative virulence factor, abstr. F-71. Abstr. 98th Annu. Meet. Am. Soc. Microbiol. 1998. American Society for Microbiology, Washington, D.C.
50. Granger, D. L.,, J. R. Perfect,, and D. T. Durack. 1985. Virulence of Cryptococcus neoformans: regulation of capsule synthesis by carbon dioxide. J. Clin. Invest. 76: 508– 516.
51. Hirano, A.,, H. M. Zimmerman,, and S. Levine. 1965. The fine structure of cerebral fluid accumulation. VII. Reactions of astrocytes to cryptococcal polysaccharide implantation. J. Neurol 24: 386– 396.
52. Hirano, A.,, H. M. Zimmerman,, and S. Levine. 1964. The fine structure of cerebral fluid accumulation. III. Extracellular spread of cryptococcal polysaccharides in the acute stage. Am. J. Pathol 46: 1– 11.
53. Hirano, A.,, H. M. Zimmerman,, and S. Levine. 1964. Fine structure of cerebral fluid accumulation. V. Transfer of fluid from extracellular compartments in acute phase of cryptococcal polysaccharide lesions. Arch. Neurol 11: 632– 641.
54. Hirano, A.,, H. M. Zimmerman,, and S. Levine. 1965. Fine structure of cerebral fluid accumulation. VI. Intracellular accumulation of fluid and cryptococcal polysaccharide in oligodendria. Arch. Neurol 12: 189– 196.
55. Hogan, L. H.,, B. S. Klein,, and S. M. Levitz. 1996. Virulence factors of medically important fungi. Clin. Microbiol Rev. 9: 469– 488.
56. Huffnagle, G. B.,, G. H. Chen,, J. L. Curtis,, R. A. McDonald,, R. M. Streiter,, and G. B. Toews. 1995. Down-regulation of the different phase of T cell-mediated pulmonary inflammation and immunity by a high melanin-producing strain of Cryptococcus neoformans. J. Immunol 155: 3507– 3516.
57. Ibrahim, A. S.,, S. G. Filler,, M. S. Alcouloumre,, T. R. Kozel,, J. E. Edwards,, and M. A. Ghannoum. 1995. Adherence to and damage of endothelial cells by Cryptococcus neoformans in vitro: role of the capsule. Infect. Immun. 63: 4368– 4374.
58. Ideka, R.,, T. Shinoda,, T. Morita,, and E. S. Jacobson. 1993. Characterization of a phenoloxidase from Cryptococcus neoformans var. neoformans. Microbiol Immunol 37: 759– 764.
59. Irokanulo, E. A.,, and C. O. Akveshi. 1995. Virulence of Cryptococcus neoformans serotypes A,B,C, and D for four mouse strains. J. Med. Microbiol. 43: 289– 293.
60. Ito, S., 1993. Biochemistry and physiology of melanin, p. 33– 59. In N. Levine (ed.), Pigmentation and Pigmentory Disorders. CRC Press, Ann Arbor, Mich.
61. Itoh, T.,, and H. Kaneko. 1977. The in vivo incorporation of 32P-labeled orthophosphate into pyrophosphatidic acid and other phospholipids of Cryptococcus neoformans through cell growth. Lipids 12: 804– 813.
62. Itoh, T.,, H. Waki,, and H. Kaneko. 1975. Changes of lipid composition with growth phase of Cryptococcus neoformans. Agric. Biol. Chem. 39: 2365– 2371.
63. Iwata, K.,, T. Yamashita,, M. Ohsumi,, M. Baba,, N. Naito,, A. Taki,, and N. Yamada. 1990. Comparative morphological and biological studies on itraconazole- and ketoconazole-resistant mutants of Cryptococcus neoformans. J. Med. Vet. Mycol 28: 77– 90.
64. Jacobson, E. S.,, and G. M. Compton. 1996. Discordant regulation of phenoloxidase and capsular polysaccharide in Cryptococcus neoformans. J. Med. Vet. Mycol. 34: 289– 291.
65. Jacobson, E. S.,, and H. S. Emery. 1991. Catecholamine uptake, melanization, and oxygen toxicity in Cryptococcus neoformans. J. Bacteriol. 173: 401– 403.
66. Jacobson, E. S.,, N. D. Jenkins,, and J. M. Todd. 1994. Relationship between superoxide dismutase and melanin in a pathogenic fungus. Infect Immun. 62: 4085– 4086.
67. Jacobson, E. S.,, and M. J. Petro. 1987. Extracellular iron chelation in Cryptococcus neoformans. J. Med. Vet. Mycol. 25: 415– 418.
68. Jacobson, E. S.,, and S. B. Tinnell. 1993. Antioxidant function of fungal melanin. J. Bacteriol. 175: 7102– 7104.
69. Jacobson, E. S.,, and S. E. Vartivarian. 1992. Iron assimilation in Cryptococcus neoformans. J. Med. Vet. Mycol. 30: 443– 450.
70. Kagaya, K.,, T. Yamada,, Y. Miyakawa,, Y. Fukazawa,, and S. Saito. 1985. Characterization of pathogenic constituents of Cryptococcus neoformans strains. Microbiol. Immunol. 29: 517– 532.
71. Kao, C. J.,, and J. Schwartz. 1957. The isolation of Cryptococcus neoformans from pigeon nests. Am. J. Pathol. 27: 652– 663.
72. Keath, E. J.,, A. A. Painter,, G. S. Kobayashi,, and G. Medoff. 1989. Variable expression of a yeast-phase-specific gene in Histoplasma capsulatum strains differing in thermotol-erance and virulence. Infect. Immun. 57: 1384– 1390.
73. Kirsch, D. R.,, and R. R. Whitney. 1991. Pathogenicity of Candida albicans auxotrophic mutants in experimental infections. Infect. Immun. 59: 3297– 3300.
74. Kojima, Y.,, Y. Tsukuda,, K. Kawai,, A. Tsukamoto,, J. Sugiura,, M. Sakaino,, and Y. Kita. 1990. Cloning, sequence analysis and expression of lignolytic phenoloxidase genes of the white-rot basidiomycete coriolus hirsutus. J. Biol. Chem. 265: 15224– 15230.
75. Kovacs, J. A.,, A. A. Kovacs,, M. Polis,, W. C. Wright,, V. J. Gill,, C. U. Tuazon,, E. P. Gelmann,, H. C. Lane,, R. Longfield,, G. Overturf,, A. M. Macher,, A. S. Fauci,, J. E. Parrillo,, J. E. Bennett,, and H. Masur. 1985. Cryptococcosis in the acquired immunodeficiency syndrome. Ann. Intern. Med. 103: 533– 538.
76. Kozel, T. R. 1995. Virulence factors of Cryptococcus neoformans. Trends Microbiol. 3: 295– 299.
77. Kozel, T. R.,, and E. C. Gotschlich. 1982. The capsule of Cryptococcus neoformans passively inhibits phagocytosis of the yeast by macrophages. J. Immunol. 129: 1675– 1680.
78. Kozel, T. R.,, W. F. Gulley,, and J. Cazin, Jr. 1977. Immune response to Cryptococcus neoformans soluble polysaccharide: immunological unresponsiveness. Infect. Immun. 18: 701– 707.
79. Kozel, T. R.,, G. S. T. Pfrommer,, A. S. Guerlain,, B. A. Highison,, and G. J. Highison. 1988. Role of the capsule in phagocytosis of Cryptococcus neoformans. Rev. Infect. Dis. 10: S436– S439.
80. Kwon-Chung, K. J.,, J. C. Edman,, and B. L. Wickes. 1992. Genetic association of mating types and virulence in Cryptococcus neoformans. Infect. Immun. 60: 602– 605.
81. Kwon-Chung, K. J.,, W. B. Hill,, and J. E. Bennett. 1981. New, special stain for histopathological diagnosis of cryptococcosis. J. Clin. Microbiol. 13: 383– 387.
82. Kwon-Chung, K. J.,, I. Polacheck,, and T. J. Popkin. 1982. Melanin-lacking mutants of Cryptococcus neoformans and their virulence for mice. J. Bacteriol. 150: 1414– 1421.
83. Kwon-Chung, K. J.,, and J. C. Rhodes. 1986. Encapsulation and melanin formation as indicators of virulence in Cryptococcus neoformans. Infect. Immun. 51: 218– 223.
84. Kwon-Chung, K.J.,, A. Varma,, J. C. Edman,, and J. E. Bennett 1992. Selection of Ura5 and Ura3 mutants from the two varieties of Cryptococcus neoformans on 5-fluoroorotic acid medium. J. Med. Vet. Mycol. 30: 61– 69.
85. Kwon-Chung, K. J.,, B. L. Wickes,, L. Stockman,, G. D. Roberts,, D. Ellis,, and D. H. Howard. 1992. Virulence, serotype and molecular characteristics of environmental strains of Cryptococcus neoformans var gattii. Infect. Immun. 60: 1869– 1874.
86. Lazera, M. S.,, F. D. A. Pires,, L. Camillo-Coura,, M. M. Nishikawa,, C. C. F. Bezerra,, L. Trilles,, and B. Wanke. 1996. Natural habitat of Cryptococcus neoformans var. neoformans in decaying wood forming hollows in living trees. J. Med. Vet. Mycol. 34: 127– 131.
87. Levitz, S. M.,, and D. J. DiBenedetto. 1989. Paradoxical role of capsule in murine bronchoalveolar macrophage-mediated killing of Cryptococcus neoformans. J. Immunol. 142: 659– 665.
88. Li, A.,, and S. Wu. 1992. An urease negative Cryptococcus neoformans. Acta Microbiol. Sin. 32: 68– 71.
89. Liang, P.,, and A. B. Pardee. 1992. Differential display of eucaryotic messenger RNA by means of the polymerase chain reaction. Science 257: 967– 971.
90. Littman, M. L.,, and E. Tsubura. 1959. Effect of degree of encapsulation upon virulence of Cryptococcus neoformans. Proc. Soc. Exp. Biol Med. 101: 773– 776.
91. Lodge, J. K.,, E. Jackson-Machelski,, D. L. Toffaletti,, J. R. Perfect,, and J. I. Gordon. 1994. Targeted gene replacement demonstrates that myristoyl CoA: protein N-myristoyl-transferase is essential for the viability of Cryptococcus neoformans. Proc. Natl Acad. Sci. USA 91: 12008– 12012.
92. Lodge, J. K.,, R. L. Johnson,, R. A. Weinberg,, and J. I. Gordon. 1994. Comparison of myristoyl-CoA: protein N-myristoyl transferases from three pathogenic fungi: Cryptococcus neoformans, Histoplasma capsulatum, and Candida albicans. J. Biol. Chem. 269: 2996– 3010.
93. Macher, A. M.,, J. E. Bennett,, J. E. Gadek,, and M. M. Frank. 1978. Complement depletion in cryptococcal sepsis. J. Immunol. 120: 1686– 1690.
97. 93a. Madani, N. D.,, P. J. Malloy,, P. Rodriquez-Pombo,, A. V. Krishnan,, and D. Feldman. 1994. Candida albicans estrogen-binding protein gene encodes an oxidoreductase that is inhibited by estradiol. Proc. Natl Acad. Sci. USA 91: 922– 926.
94. Mahan, M. J.,, J. M. Slauch,, and J. J. Mekalanos. 1993. Selection of bacterial virulence genes that are specifically induced in host tissues. Science 259: 686– 688.
95. Martinez-Marino, B.,, and B. Bolanos. 1995. Characterization of a cytoplasmic protein that inhibits phagocytosis, abstr. F9. Abstr. 95th Annu. Meet. Am. Soc. Microbiol. 1995. American Society for Microbiology, Washington, DC.
96. Megson, G. M.,, D. A. Stevens,, J. R. Hamilton,, and D. W. Denning. 1996. D-Mannitol in cerebrospinal fluid of patients with AIDS and cryptococcal meningitis. J. Clin. Microbiol 34: 218– 221.
97. Merkel, G.,, B. Scofield,, F. Rescoria,, and R. Yang. 1994. Comparison between in vitro glial cell adherence and internalization of nonencapsulated strains of Cryptococcus neoformans. J. Med. Vet. Mycol 32: 361– 372.
98. Merkel, G.,, B. Scofield,, F. Rescoria,, R. Yang,, and J. Grosfeld. 1995. Reduced recovery of Cryptococcus neoformans adherent mutant from a rat model of cryptococcosis. Can. J. Microbiol 41: 428– 432.
99. Merkel, G. J.,, and B. A. Scofield. 1993. Conditions affecting the adherence of Cryptococcus neoformans to rat glial and lung cells in vitro. J. Med. Vet. Mycol. 31: 55– 64.
100. Miller, M. E.,, and T. G. Mitchell. 1991. Killing of Cryptococcus neoformans strains by human neutrophils and monocytes. Infect. Immun. 59: 24– 28.
101. Montero-Gei, E., and F. Avardo. 1978. Clinical and epidemiological aspects of cryptococcosis in Costa Rica. The black and white yeasts. Proceedings of the 9th International Conference on Mycoses. Pan American Health Organization, Washington, D.C.
102. Moore, T. D. E.,, and J. D. Edman. 1993. The alpha mating type locus of Cryptococcus neoformans contains a peptide pheromone gene. Mol Cell. Biol 13: 1962– 1970.
103. Murphy, J. W.G.,, and C. Cozad. 1972. Immunological unresponsiveness induced by cryptococcal polysaccharide assayed by the hemolytic plaque technique. Infect. Immun. 5: 896– 901.
104. Neilson, J. B.,, M. H. Ivey,, and G. S. Bulmer. 1978. Cryptococcus neoformans: pseudohyphal forms surviving culture with Acanthamoeba polyphaga. Infect. Immun. 20: 262– 266.
105. Nosanchuk, J. D.,, and A. Casadevall. 1997. Cellular charge of Cryptococcus neoformans: contributions from the capsular polysaccharide, melanin, and monoclonal antibody binding. Infect. Immun. 65: 1836– 1841.
106. Nyhus, K. J.,, and E. S. Jacobson. 1996. Reduction of ferric iron by Cryptococcus neoformans, abstr. 1.4:148. 3rd International Conference on Cryptococcus and Cryptococcosis, Paris.
107. Odom, A.,, M. Del Poeta,, J. Perfect,, and J. Heitman. 1997. The immunosuppressant FK506 and its non-immunosuppressive analog L-685,818 are toxic to Cryptococcus neoformans by inhibition of a common target protein. Antimicrob. Agents Chemother. 41: 156– 161.
108. Odom, A.,, S. Muir,, E. Lim,, D. L. Toffaletti,, J. R. Perfect,, and J. Heitman. 1997. Calcineurin is required for virulence of Cryptococcus neoformans. EMBO J. 16: 2576– 2589.
109. Perfect, J. R. 1996. Fungal virulence genes as targets for antifungal chemotherapy. Antimicrob. Agents Chemother. 40: 1577– 1583.
110. Perfect, J. R. 1997. Differential expressions and virulence, abstr. S125. 13th Congress of International Society for Human and Animal Mycology, Italy.
111. Perfect, J. R.,, and D. T. Durack. 1985. Effects of cyclosporine in experimental cryptococcal meningitis. Infect. Immun. 50: 22– 26.
112. Perfect, J. R.,, S. D. R. Lang,, and D. T. Durack. 1980. Chronic cryptococcal meningitis: a new experimental model in rabbits. Am. J. Pathol. 101: 177– 194.
113. Perfect, J. R.,, T. H. Rude,, B. Wong,, T. Flynn,, V. Chaturvedi,, and W. Niehaus. 1996. Identification of a Cryptococcus neoformans gene that directs expression of the cryptic Saccharomyces cerevisiae mannitol dehydrogenase gene. J. Bacteriol. 178: 5257– 5262.
114. Perfect, J. R.,, D. L. Toffaletti,, and T. H. Rude. 1993. The gene encoding for phosphori-bosylaminoimidazole carboxylase (ADE2) is essential for growth of Cryptococcus neoformans in cerebrospinal fluid. Infect. Immun. 61: 4446– 4451.
115. Perfect, J. R.,, B. Wong,, Y. Chang,, K. J. Kwon-Chung,, and P. R. Williamson. 1998. Cryptococcus neoformans: virulence and host defenses. Med. Mycol. 36, in press.
116. Petter, R.,, A. Varma,, T. Boekhout,, S. Salas,, B. Davis,, and K. J. Kwon-Chung. 1996. Molecular divergence of the virulence factors of Filobasidiella neoformans found in other heterobasidiomycetous species, abstr. 2.2:36-38. 3rd International Conference on Cryptococcus and Cryptococcosis, Paris.
117. Pettoello-Mantovani, M.,, A. Casadevall,, T. R. Kollman,, A. Rubinstein,, and H. Goldstein. 1992. Enhancement of HIV-1 infection by the capsular polysaccharide of Cryptococcus neoformans. Lancet 339: 21– 23.
118. Pettoello-Mantovani, M.,, A. Casadevall,, P. Smarnworawong,, and H. Goldstein. 1994. Enhancement of HTV Type 1 infectivity in vitro by capsular polysaccharide of Cryptococcus neoformans and Haemophilus influenzae. AIDS Res. Hum. Retroviruses 10: 1079– 1087.
119. Polacheck, I. 1991. The discovery of melanin production in C. neoformans and its impact on diagnosis and the study of virulence. Int. J. Med. Microbiol. 276: 120– 123.
120. Polacheck, I.,, V. J. Hearing,, and K. J. Kwon-Chung. 1982. Biochemical studies of phenoloxidase and utilization of catechalamines in Cryptococcus neoformans. J. Bacteriol. 150: 1212– 1220.
121. Polacheck, I.,, and K. J. Kwon-Chung. 1988. Melanogenesis in Cryptococcus neoformans. J. Gen. Microbiol. 134: 1037– 1041.
122. Polacheck, I.,, Y. Piatt,, and J. Aronovitch. 1990. Catecholamines and virulence of Cryptococcus neoformans. Infect. Immun. 58: 2919– 2922.
123. Polak, A. 1990. Melanin as a virulence factor in pathogenic fungi. Mycoses 33: 215– 224.
124. Rawat, D. S.,, H. B. Upreti,, and S. K. Das. 1984. Lipid composition of Cryptococcus neoformans. Microbiologica 7: 299– 307.
125. Regenfelder, E.,, T. Spellig,, A. Hartman,, S. Lavenstein,, M. Bolker,, and R. Kahmann. 1996. G-proteins in Ustilago maydis. Transmission of multiple signals. EMBO J. 16: 1934– 1942.
126. Retini, C.,, A. Vecchiarelli,, C. Monari,, C. Tascini,, F. Bistoni,, and T. R. Kozel. 1996. Capsular polysaccharide of Cryptococcus neoformans induces proinflammatory cytokine release by human neutrophils. Infect. Immun. 64: 2897– 2903.
127. Rhodes, J. C.,, and D. H. Howard. 1980. Isolation and characterization of arginine auxotrophs of Cryptococcus neoformans. Infect. Immun. 27: 910– 914.
128. Rhodes, J. C.,, I. Polacheck,, and K. J. Kwon-Chung. 1982. Phenoloxidase activity and virulence in isogenic strains of Cryptococcus neoformans. Infect. Immun. 36: 1175– 1184.
129. Ro, J. Y.,, S. S. Lee,, and A. G. Ayala. 1987. Advantage of Fontana-Masson stain in capsule-deficient cryptococcal infection. Arch. Pathol. Lab. Med. 111: 53– 57.
130. Rosas, A. L.,, and A. Casadevall. 1997. Melanization affects susceptibility of Cryptococcus neoformans to heat and cold. FEMS Microbiol. Lett. 153: 265– 272.
131. Ruane, P. J.,, L. J. Walker,, and W. L. George. 1988. Disseminated infection caused by urease-negative Cryptococcus neoformans. J. Clin. Microbiol. 26: 2224– 2226.
132. Rude, T. H.,, and J. R. Perfect. 1994. Isolation and identification of several site-specific genes of Cryptococcus neoformans differentially expressed in the CNS, abstr. F49. Abstr. 94th Annu. Meet. Am. Soc. Microbiol. 1994. American Society for Microbiology, Washington, D.C.
133. Salas, S. D.,, J. E. Bennett,, K. J. Kwon-Chung,, J. R. Perfect,, and P. R. Williamson. 1996. Effect of the laccase gene, CNLAC1, on virulence of Cryptococcus neoformans. J. Exp. Med. 184: 377– 386.
134. Schena, M.,, D. Shalon,, R. W. Davis,, and P. O. Brown. 1995. Quantitative monitoring of gene expression patterns with a complementary DNA microassay. Science 270: 467– 470.
135. Shaw, C.E.,, and L. Kapica. 1972. Production of diagnosis pigment by phenoloxidase activity of Cryptococcus neoformans. Appl. Environ. Microbiol. 24: 824– 830.
136. Sherman, E.,, G. R. Fink,, and J. B. Hicks. 1987. Laboratory Course Manual for Methods in Yeast Genetics. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.
137. Small, J. M.,, and T. G. Mitchell. 1986. Binding of purified and radioiodinated capsular polysaccharides from Cryptococcus neoformans serotype A strains to capsule-free mutants. Infect. Immun. 54: 742– 750.
138. Small, J. M.,, and T. G. Mitchell. 1989. Strain variation in the antiphagocytic activity of capsular polysaccharides from Cryptococcus neoformans serotype A. Infect. Immun. 57: 3751– 3756.
139. Steele, P. E. 1991. Current concepts of fungal virulence. Adv. Pathol. Lab. Med. 4: 107– 119.
140. Still, C. N.,, and E. S. Jacobson. 1983. Recombinational mapping of capsule mutations in Cryptococcus neoformans. J. Bacteriol. 156: 460– 462.
141. Tolkacheva, T.,, T. P. McNamara,, E. Piekarz,, and W. Courchesne. 1994. Cloning of a Cryptococcus neoformans gene, GPA1, encoding a G-protein a-subunit homolog. Infect. Immun. 62: 2849– 2856.
142. Torres-Guererro, H.,, and J. C. Edman. 1994. Melanin-deficient mutants of Cryptococcus neoformans. J. Med. Vet. Mycol. 32: 303– 313.
143. Upreti, H. B.,, D. S. Rawat,, and S. K. Das. 1984. Virulence, capsule size and lipid composition interrelation of Cryptococcus neoformans. Microbiologica 7: 371– 374.
144. Vadkertiova, R.,, and E. Slavikova. 1995. Killer activity of yeasts isolated from the water environment. Can. J. Microbiol. 41: 759– 766.
145. Valentine, J. S.,, and E. B. Gralla. 1997. Delivering copper inside yeast and human cells. Science 278: 817– 818.
146. Van Cutsem, J.,, J. Fransen,, F. Van Gerven,, and P. A. J. Janssen. 1986. Experimental cryptococcosis: dissemination of Cryptococcus neoformans and dermatropism in guinea pigs. Mykosen 29: 561– 575.
147. Varma, A.,, J. C. Edman,, and K. J. Kwon-Chung. 1992. Molecular and genetic analysis of URA5 transformants of Cryptococcus neoformans. Infect. Immun. 60: 1101– 1108.
148. Vartivarian, S. E.,, E. J. Anaissie,, R. E. Cowart,, H. A. Sprigg,, M. J. Tingler,, and E. S. Jacobson. 1993. Regulation of cryptococcal capsular polysaccharide by iron. J. Infect. Dis. 167: 186– 190.
149. Vecchiarelli, A.,, C. Retini,, C. Monari,, C. Tascini,, F. Bistoni,, and T. R. Kozel. 1996. Purified capsular polysaccharide of Cryptococcus neoformans induces interleukin-10 secretion by human monocytes. Infect. Immun. 64: 2846– 2849.
150. Vecchiarelli, A.,, C. Retini,, D. Pietrella,, C. Monari,, C. Tascini,, T. Beccari,, and T. R. Kozel. 1995. Down-regulation by cryptococcal polysaccharide of tumor necrosis factor alpha and interleukin-1 beta secretion from human monocytes. Infect. Immun. 63: 2919– 2923.
151. Velculescu, V. E.,, L. Zhang,, B. Vogelstein,, and K. W. Kinzler. 1995. Serial analysis of gene expression. Science 270: 484r487.
152. Vidotto, V.,, A. Sinicco,, D. Di Fraia,, S. Cardaropoli,, S. Aoki,, and S. Ito-Kuwa. 1997. Phospholipase activity in Cryptococcus neoformans. Mycopathologia 136: 119– 123.
153. Vincent, V. L.,, and L. S. Klig. 1995. Unusual effect of myo-inositol on phospholipid biosynthesis in Cryptococcus neoformans. Microbiology 141: 1829– 1837.
154. Wang, Y.,, P. Aisen,, and A. Casadevall. 1995. Cryptococcus neoformans melanin and virulence: mechanism of action. Infect. Immun. 63: 3131– 3136.
155. Wang, Y.,, P. Aisen,, and A. Casadevall. 1996. Melanin, melanin "ghosts," and melanin composition in Cryptococcus neoformans. Infect. Immun. 64: 2420– 2424.
156. Wang, Y.,, and A. Casadevall. 1994. Decreased susceptibility of melanized Cryptococcus neoformans to UV light. Appl. Environ. Microbiol. 60: 3864– 3866.
157. Wang, Y.,, and A. Casadevall. 1994. Susceptibility of melanized and nonmelanized Cryptococcus neoformans to nitrogen- and oxygen-derived oxidants. Infect. Immun. 64: 3004– 3007.
158. Wang, Y.,, and A. Casadevall. 1994. Growth of Cryptococcus neoformans in presence of L-dopa decreases its susceptibility to amphotericin B. Antimicrob. Agents Chemother. 38: 2648– 2650.
159. Wickes, B. L.,, U. Edman,, and J. C. Edman. 1997. The Cryptococcus neoformans STE12 gene: a putative Saccharomyces cerevisiae STE12 homologue that is mating type specific. Mol. Microbiol. 26: 951– 960.
160. Wickes, B. L.,, M. E. Mayorga,, U. Edman,, and J. C. Edman. 1996. Dimorphism and haploid fruiting in Cryptococcus neoformans association with the alpha-mating type. Proc. Natl. Acad. Sci. USA 93: 7327– 7331.
161. Williamson, P. 1997. Laccase and melanin in the pathogenesis of Cryptococcus neoformans. Front. Biosci. 2: 99– 107.
162. Williamson, P. R. 1994. Biochemical and molecular characterization of the diphenol oxidase of Cryptococcus neoformans: identification as a laccase. J. Bacteriol. 176: 656– 664.
163. Williamson, P. R.,, and S. Zhang. 1996. Transcriptional regulators of CNLAC1, abstr. 1-4:16-17. 3rd International Conference on Cryptococcus and Cryptococcosis, Paris.
164. Wong, B.,, J. R. Perfect,, S. Beggs,, and K. A. Wright. 1990. Production of the hexitol D-mannitol by Cryptococcus neoformans in vitro and in rabbits with experimental meningitis. Infect. Immun. 58: 1664– 1670.

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