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Cryptococcus gattii, No Longer an Accidental Pathogen?

  • Genomics and Pathogenesis (S Shoham, Section Editor)
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Abstract

Cryptococcus gattii is an environmentally occurring pathogen that is responsible for causing cryptococcosis marked by pneumonia and meningoencephalitis in humans and animals. C. gattii can form long-term associations with trees and soil resulting in the production of infectious propagules (spores and desiccated yeast). The ever-expanding number of reports of clinical and environmental isolation of C. gattii in temperate climates strongly imply that C. gattii occurs worldwide. The key ability of yeast and spores to enter, survive, multiply, and exit host cells, and to infect immunocompetent hosts distinguishes C. gattii as a primary pathogen and suggests evolution of C. gattii pathogenesis as a result of interaction with plants and other organisms in its environmental niche. Here we summarize the historical literature on C. gattii and recent literature supporting the worldwide occurrence of the primary pathogen C. gattii.

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References

Papers of particular interest, published recently have been highlighted as: • Of importance •• Of major importance

  1. Vanbreuseghem R, Takashio M. An atypical strain of Cryptococcus neoformans (San Felice) Vuillemin 1894. II. Cryptococcus neoformans var. gattii var. nov. Ann Soc Belg Med Trop Parasitol Mycol. 1970;50:695–702.

    CAS  Google Scholar 

  2. Sorrell TC. Cryptococcus neoformans variety gattii. Med Mycol. 2001;39:155–68.

    PubMed  CAS  Google Scholar 

  3. Kwon-Chung KJ. A new species of Filobasidiella, the sexual state of Cryptococcus neoformans B and C serotypes. Mycologia. 1976;68:943–6.

    PubMed  CAS  Google Scholar 

  4. Kwon-Chung KJ, Boekhout T, Fell JW, Diaz M. Proposal to conserve the name Cryptococcus gattii against C. hondurianus and C. bacillisporus (Basidiomycota, Hymenomycetes, Tremellomycetidae). Taxon. 2002;51:804–6.

    Article  Google Scholar 

  5. •• Heitman J, Kozel TR, Kwon-Chung J, Perfect JR, Casadevall A (eds). Cryptococcus: from human pathogen to model yeast. Washington, DC: ASM Press; 2011. Comprehensive book on Cryptococcus. Assembles chapters from a contingent of international experts on the up to date research on Cryptococcus.

  6. Ngamskulrungroj P, Price J, Sorrell T, Perfect JR, Meyer W. Cryptococcus gattii virulence composite: candidate genes revealed by microarray analysis of high and less virulent Vancouver island outbreak strains. PLoS One. 2011;6:e16076.

    Article  PubMed  CAS  Google Scholar 

  7. Ngamskulrungroj P, Chang Y, Roh J, Kwon-Chung KJ. Differences in nitrogen metabolism between Cryptococcus neoformans and C. gattii, the two etiologic agents of Cryptococcosis. PLoS One. 2012;7:e34258.

    Article  PubMed  CAS  Google Scholar 

  8. Hoang LM, Maguire JA, Doyle P, Fyfe M, Roscoe DL. Cryptococcus neoformans infections at Vancouver Hospital and Health Sciences Centre (1997–2002): epidemiology, microbiology and histopathology. J Med Microbiol. 2004;53:935–40.

    Article  PubMed  Google Scholar 

  9. Stephen C, Lester S, Black W, Fyfe M, Raverty S. Multispecies outbreak of cryptococcosis on southern Vancouver Island, British Columbia. Can Vet J. 2002;43:792–4.

    PubMed  Google Scholar 

  10. Kidd SE, Hagen F, Tscharke RL, Huynh M, Bartlett KH, Fyfe M, et al. A rare genotype of Cryptococcus gattii caused the cryptococcosis outbreak on Vancouver Island (British Columbia, Canada). Proc Natl Acad Sci U S A. 2004;101:17258–63.

    Article  PubMed  CAS  Google Scholar 

  11. Kidd SE, Guo H, Bartlett KH, Xu J, Kronstad JW. Comparative gene genealogies indicate that two clonal lineages of Cryptococcus gattii in British Columbia resemble strains from other geographical areas. Eukaryot Cell. 2005;4:1629–38.

    Article  PubMed  CAS  Google Scholar 

  12. Pfeiffer T, Ellis D. Environmental isolation of Cryptococcus neoformans var. gattii from California. J Infect Dis. 1991;163:929–30.

    Article  PubMed  CAS  Google Scholar 

  13. MacDougall L, Kidd SE, Galanis E, Mak S, Leslie MJ, Cieslak PR, et al. Spread of Cryptococcus gattii in British Columbia, Canada, and detection in the Pacific Northwest, USA. Emerg Infect Dis. 2007;13:42–50.

    Article  PubMed  Google Scholar 

  14. •• 3rd Byrnes EJ, Bildfell RJ, Frank SA, Mitchell TG, Marr KA, Heitman J. Molecular evidence that the range of the Vancouver Island outbreak of Cryptococcus gattii infection has expanded into the Pacific Northwest in the United States. J Infect Dis. 2009;199:1081–6. Demonstrated C. gattii expansion outside Vancouver, BC, into the USA.

    Article  PubMed  Google Scholar 

  15. Velagapudi R, Hsueh YP, Geunes-Boyer S, Wright JR, Heitman J. Spores as infectious propagules of Cryptococcus neoformans. Infect Immun. 2009;77:4345–55.

    Article  PubMed  CAS  Google Scholar 

  16. Giles SS, Dagenais TR, Botts MR, Keller NP, Hull CM. Elucidating the pathogenesis of spores from the human fungal pathogen Cryptococcus neoformans. Infect Immun. 2009;77:3491–500.

    Article  PubMed  CAS  Google Scholar 

  17. Botts MR, Giles SS, Gates MA, Kozel TR, Hull CM. Isolation and characterization of Cryptococcus neoformans spores reveal a critical role for capsule biosynthesis genes in spore biogenesis. Eukaryot Cell. 2009;8:595–605.

    Article  PubMed  CAS  Google Scholar 

  18. Ruiz A, Neilson JB, Bulmer GS. Control of Cryptococcus neoformans in nature by biotic factors. Sabouraudia. 1982;20:21–9.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  20. Malliaris SD, Steenbergen JN, Casadevall A. Cryptococcus neoformans var. gattii can exploit Acanthamoeba castellanii for growth. Med Mycol. 2004;42:149–58.

    Article  PubMed  Google Scholar 

  21. Steenbergen JN, Nosanchuk JD, Malliaris SD, Casadevall A. Cryptococcus neoformans virulence is enhanced after growth in the genetically malleable host Dictyostelium discoideum. Infect Immun. 2003;71:4862–72.

    Article  PubMed  CAS  Google Scholar 

  22. Alvarez M, Casadevall A. Phagosome extrusion and host-cell survival after Cryptococcus neoformans phagocytosis by macrophages. Curr Biol. 2006;16:2161–5.

    Article  PubMed  CAS  Google Scholar 

  23. • Springer DJ, Ren P, Raina R, Dong Y, Behr MJ, McEwen BF, et al. Extracellular fibrils of pathogenic yeast Cryptococcus gattii are important for ecological niche, murine virulence and human neutrophil interactions. PLoS One. 2010;5:e10978. First to demonstrate increased virulence of C. gattii from growth on plant material.

    Article  PubMed  CAS  Google Scholar 

  24. Alvarez M, Burn T, Luo Y, Pirofski LA, Casadevall A. The outcome of Cryptococcus neoformans intracellular pathogenesis in human monocytes. BMC Microbiol. 2009;9:51.

    Article  PubMed  CAS  Google Scholar 

  25. Voelz K, Lammas D, May R. Cytokine signaling regulates outcome of intracellular macrophage parasitism by Cryptococcus neoformans. Infect Immun. 2009;77(8):3450–57.

    Google Scholar 

  26. •• Ma H, Hagen F, Stekel DJ, Johnston SA, Sionov E, Falk R, et al. The fatal fungal outbreak on Vancouver Island is characterized by enhanced intracellular parasitism driven by mitochondrial regulation. Proc Natl Acad Sci U S A. 2009;106:12980–5. A comprehensive study linking tubular mitochondria, mitochondrial regulation and enhanced intracellular proliferation of C. gattii.

    Article  PubMed  CAS  Google Scholar 

  27. •• 3rd Byrnes EJ, Li W, Lewit Y, Ma H, Voelz K, Ren P, et al. Emergence and pathogenicity of highly virulent Cryptococcus gattii genotypes in the northwest United States. PLoS Pathog. 2010;6:e1000850. MLST study including many isolates that provides evidence of clonal expansion and the emergence of novel genotypes. Also distinguishes VGIIc as a highly virulent type by murine virulence and intracellular proliferation.

    Article  PubMed  CAS  Google Scholar 

  28. Charlier C, Nielsen K, Daou S, Brigitte M, Chretien F, Dromer F. Evidence of a role for monocytes in dissemination and brain invasion by Cryptococcus neoformans. Infect Immun. 2009;77:120–7.

    Article  PubMed  CAS  Google Scholar 

  29. Evans EE. The antigenic composition of Cryptococcus neoformans. I. A serologic classification by means of the capsular and agglutination reactions. J Immunol. 1950;64:423–30.

    PubMed  CAS  Google Scholar 

  30. Wilson DE, Bennett JE, Bailey JW. Serologic grouping of Cryptococcus neoformans. Proc Soc Exp Biol Med. 1968;127:820–3.

    PubMed  CAS  Google Scholar 

  31. Kwon-Chung KJ, Polacheck I, Bennett JE. Improved diagnostic medium for separation of Cryptococcus neoformans var. neoformans (serotypes A and D) and Cryptococcus neoformans var. gattii (serotypes B and C). J Clin Microbiol. 1982;15:535–7.

    PubMed  CAS  Google Scholar 

  32. Meyer W, Castaneda A, Jackson S, Huynh M, Castaneda E. Molecular typing of IberoAmerican Cryptococcus neoformans isolates. Emerg Infect Dis. 2003;9:189–95.

    Article  PubMed  Google Scholar 

  33. Ellis DH, Pfeiffer TJ. Natural habitat of Cryptococcus neoformans var. gattii. J Clin Microbiol. 1990;28:1642–4.

    PubMed  CAS  Google Scholar 

  34. Vogel RA. The indirect fluorescent antibody test for the detection of antibody in human cryptococcal disease. J Infect Dis. 1966;116:573–80.

    Article  PubMed  CAS  Google Scholar 

  35. Boekhout T, van Belkum A, Leenders AC, Verbrugh HA, Mukamurangwa P, Swinne D, et al. Molecular typing of Cryptococcus neoformans: taxonomic and epidemiological aspects. Int J Syst Bacteriol. 1997;47:432–42.

    Article  PubMed  CAS  Google Scholar 

  36. Meyer W, Mitchell TG, Freedman EZ, Vilgalys R. Hybridization probes for conventional DNA fingerprinting used as single primers in the polymerase chain reaction to distinguish strains of Cryptococcus neoformans. J Clin Microbiol. 1993;31:2274–80.

    PubMed  CAS  Google Scholar 

  37. • Chowdhary A, Randhawa HS, Sundar G, Kathuria S, Prakash A, Khan Z, et al. In vitro antifungal susceptibility profiles and genotypes of 308 clinical and environmental isolates of Cryptococcus neoformans var. grubii and Cryptococcus gattii serotype B from north-western India. J Med Microbiol. 2011;60:961–7. A detailed analysis and comparison of different species and molecular types demonstrating differences in antifungal susceptibility.

    Article  PubMed  Google Scholar 

  38. Boekhout T, Theelen B, Diaz M, Fell JW, Hop WCJ, Abeln ECA, et al. Hybrid genotypes in the pathogenic yeast Cryptococcus neoformans. Microbiology. 2001;147:891–907.

    PubMed  CAS  Google Scholar 

  39. Marra RE, Huang JC, Fung E, Nielsen K, Heitman J, Vilgalys R, et al. A genetic linkage map of Cryptococcus neoformans variety neoformans serotype D (Filobasidiella neoformans). Genetics. 2004;167:619–31.

    Article  PubMed  CAS  Google Scholar 

  40. • Hagen F, Illnait-Zaragozi M-T, Bartlett KH, Swinne D, Geertsen E, Klaassen CHW, et al. In vitro antifungal susceptibilities and amplified fragment length polymorphism genotyping of a worldwide collection of 350 clinical, veterinary, and environmental Cryptococcus gattii isolates. Antimicrob Agents Chemother. 2010;54:5139–45. A detailed analysis demonstrating differences in antifungal susceptibility of large collection of C. gattii isolates.

    Article  PubMed  CAS  Google Scholar 

  41. Bovers M, Hagen F, Kuramae EE, Hoogveld HL, Dromer F, St-Germain G, et al. AIDS patient death caused by novel Cryptococcus neoformans x C. gattii hybrid. Emerg Infect Dis. 2008;14:1105–8.

    Article  PubMed  CAS  Google Scholar 

  42. Aminnejad M, Diaz M, Arabatzis M, Castaneda E, Lazera M, Velegraki A, et al. Identification of novel hybrids between Cryptococcus neoformans var. grubii VNI and Cryptococcus gattii VGII. Mycopathologia. 2012;173:337–46.

    Article  PubMed  CAS  Google Scholar 

  43. Bovers M, Hagen F, Kuramae EE, Diaz MR, Spanjaard L, Dromer F, et al. Unique hybrids between the fungal pathogens Cryptococcus neoformans and Cryptococcus gattii. FEMS Yeast Res. 2006;6:599–607.

    Article  PubMed  CAS  Google Scholar 

  44. Hagen F, Colom MF, Swinne D, Tintelnot K, Iatta R, Montagna MT, et al. Autochthonous and dormant C. gattii infections in Europe. Emerg Infect Dis. 2012;V18(10):1618–20.

    Google Scholar 

  45. • Romeo O, Scordino F, Criseo G. Environmental isolation of Cryptococcus gattii serotype B, VGI/MATalpha strains in southern Italy. Mycopathologia. 2011;171:423–30. Environmental isolation of C. gattii from Italy.

    Article  PubMed  Google Scholar 

  46. • Chowdhary A, Randhawa HS, Boekhout T, Hagen F, Klaassen CH, Meis JF. Temperate climate niche for Cryptococcus gattii in Northern Europe. Emerg Infect Dis. 2012;18:172–4. First environmental isolation of C. gattii VGI from the Netherlands.

    Article  PubMed  Google Scholar 

  47. • Sellers B, Hall P, Cine-Gowdie S, Hays AL, Patel K, Lockhart SR, et al. Cryptococcus gattii: an emerging fungal pathogen in the Southeastern United States. Am J Med Sci. 2012;343:510–1. Expanded incidence of C. gattii VGI outside thw western USA and Canada.

    Article  PubMed  Google Scholar 

  48. 3rd Byrnes EJ, Li W, Lewit Y, Perfect JR, Carter DA, Cox GM, et al. First reported case of Cryptococcus gattii in the Southeastern USA: implications for travel-associated acquisition of an emerging pathogen. PLoS One. 2009;4:e5851.

    Article  PubMed  CAS  Google Scholar 

  49. McCulloh RJ, Phillips R, Perfect JR, Byrnes 3rd EJ, Heitman J, Dufort E. Cryptococcus gattii genotype VGI infection in New England. Pediatr Infect Dis J. 2011;30:1111–4.

    Article  PubMed  Google Scholar 

  50. • Colom MF, Hagen F, Gonzalez A, Mellado A, Morera N, Linares C, et al. Ceratonia siliqua (carob) trees as natural habitat and source of infection by Cryptococcus gattii in the Mediterranean environment. Med Mycol. 2012;50:67–73. First environmental isolation of C. gattii VGI in Spain.

    Article  PubMed  Google Scholar 

  51. Chen M, Liao WQ, Wu SX, Yao ZR, Pan WH, Liao Y. Taxonomic analysis of Cryptococcus species complex strain S8012 revealed Cryptococcus gattii with high heterogeneity on the genetics. Chin Med J. 2011;124:2051–6.

    PubMed  CAS  Google Scholar 

  52. Choi YH, Ngamskulrungroj P, Varma A, Sionov E, Hwang SM, Carriconde F, et al. Prevalence of the VNIc genotype of Cryptococcus neoformans in non-HIV-associated cryptococcosis in the Republic of Korea. FEMS Yeast Res. 2010;10:769–78.

    Article  PubMed  CAS  Google Scholar 

  53. Feng X, Yao Z, Ren D, Liao W, Wu J. Genotype and mating type analysis of Cryptococcus neoformans and Cryptococcus gattii isolates from China that mainly originated from non-HIV-infected patients. FEMS Yeast Res. 2008;8:930–8.

    Article  PubMed  CAS  Google Scholar 

  54. Matos CS, de Souza Andrade A, Oliveira NS, Barros TF. Microbiological characteristics of clinical isolates of Cryptococcus spp. in Bahia, Brazil: molecular types and antifungal susceptibilities. Eur J Clin Microbiol Infect Dis. 2012;31:1647–52.

    Article  PubMed  CAS  Google Scholar 

  55. Debourgogne A, Hagen F, Elenga N, Long L, Blanchet D, Veron V, et al. Successful treatment of Cryptococcus gattii neurocryptococcosis in a 5-year-old immunocompetent child from the French Guiana Amazon region. Rev Iberoam Micol. 2012. [Epub ahead of print]. doi:10.1016/j.riam.2012.01.008

  56. Pasa CR, Chang MR, Hans-Filho G. Post-trauma primary cutaneous cryptococcosis in an immunocompetent host by Cryptococcus gattii VGII. Mycoses. 2012;55:e1–3.

    PubMed  Google Scholar 

  57. Martins LM, Wanke B, Lazera Mdos S, Trilles L, Barbosa GG, de Macedo RC, et al. Genotypes of Cryptococcus neoformans and Cryptococcus gattii as agents of endemic cryptococcosis in Teresina, Piaui (northeastern Brazil). Mem Inst Oswaldo Cruz. 2011;106:725–30.

    PubMed  Google Scholar 

  58. Cogliati M, Chandrashekar N, Esposto MC, Chandramuki A, Petrini B, Viviani MA. Cryptococcus gattii serotype-C strains isolated in Bangalore, Karnataka, India. Mycoses. 2012;55:262–8.

    Article  PubMed  CAS  Google Scholar 

  59. Firacative C, Torres G, Rodriguez MC, Escandon P. First environmental isolation of Cryptococcus gattii serotype B, from Cucuta, Colombia. Biomedica. 2011;31:118–23.

    PubMed  Google Scholar 

  60. Olivares LR, Martinez KM, Cruz RM, Rivera MA, Meyer W, Espinosa RA, et al. Genotyping of Mexican Cryptococcus neoformans and C. gattii isolates by PCR-fingerprinting. Med Mycol. 2009;47:713–21.

    Article  PubMed  CAS  Google Scholar 

  61. Byrnes 3rd EJ, Marr KA. The outbreak of Cryptococcus gattii in western North America: epidemiology and clinical issues. Curr Infect Dis Rep. 2011;13:256–61.

    Article  PubMed  Google Scholar 

  62. • Walraven CJ, Gerstein W, Hardison SE, Wormley F, Lockhart SR, Harris JR, et al. Fatal disseminated Cryptococcus gattii infection in New Mexico. PLoS One. 2011;6:e28625. First clinical report of C. gattii in New Mexico. Evidence for a wider distribution of C. gattii.

    Article  PubMed  CAS  Google Scholar 

  63. •• Byrnes EJ, Li W, Ren P, Lewit Y, Voelz K, Fraser JA, et al. A diverse population of Cryptococcus gattii molecular type VGIII in southern Californian HIV/AIDS patients. PLoS Pathog. 2011;7:e1002205. A primary report providing a detailed account of the population structure and endemicity of C. gattii in California. Crucial in highlighting the prevalence of C. gattii VGIII in HIV + individuals of California.

    Article  PubMed  CAS  Google Scholar 

  64. Trilles L, Lazera Mdos S, Wanke B, Oliveira RV, Barbosa GG, Nishikawa MM, et al. Regional pattern of the molecular types of Cryptococcus neoformans and Cryptococcus gattii in Brazil. Mem Inst Oswaldo Cruz. 2008;103:455–62.

    Article  PubMed  CAS  Google Scholar 

  65. • Loperena-Alvarez Y, Ren P, Li X, Schoonmaker-Bopp DJ, Ruiz A, Chaturvedi V, et al. Genotypic characterization of environmental isolates of C. gattii from Puerto Rico. Mycopathologia. 2010;170:279–85. First report expanding C. gattii niche to cacti.

    Article  PubMed  Google Scholar 

  66. Litvintseva AP, Thakur R, Reller LB, Mitchell TG. Prevalence of clinical isolates of Cryptococcus gattii serotype C among patients with AIDS in Sub-Saharan Africa. J Infect Dis. 2005;192:888–92.

    Article  PubMed  CAS  Google Scholar 

  67. • Souza LKH, Souza Junior AH, Costa CR, Faganello J, Vainstein MH, Chagas ALB, et al. Molecular typing and antifungal susceptibility of clinical and environmental Cryptococcus neoformans species complex isolates in Goiania, Brazil. Mycoses. 2010;53:62–7. Demonstrates differences in sensitivity to antifungals between C. gattii molecular types.

    Article  PubMed  CAS  Google Scholar 

  68. Ngamskulrungroj P, Gilgado F, Faganello J, Litvintseva AP, Leal AL, Tsui KM, et al. Genetic diversity of the Cryptococcus species complex suggests that Cryptococcus gattii deserves to have varieties. PLoS One. 2009;4:e5862.

    Article  PubMed  CAS  Google Scholar 

  69. Katsu M, Kidd S, Ando A, Moretti-Branchini ML, Mikami Y, Nishimura K, et al. The internal transcribed spacers and 5.8S rRNA gene show extensive diversity among isolates of the Cryptococcus neoformans species complex. FEMS Yeast Res. 2004;4:377–88.

    Article  PubMed  CAS  Google Scholar 

  70. Meyer W, Aanensen DM, Boekhout T, Cogliati M, Diaz MR, Esposto MC, et al. Consensus multi-locus sequence typing scheme for Cryptococcus neoformans and Cryptococcus gattii. Med Mycol. 2009;47:1–14.

    Article  CAS  Google Scholar 

  71. •• Fraser JA, Giles SS, Wenink EC, Geunes-Boyer SG, Wright JR, Diezmann S, et al. Same-sex mating and the origin of the Vancouver Island Cryptococcus gattii outbreak. Nature. 2005;437:1360–4. First report to demonstrate the unique genetics and clonal spread of C. gattii strains associated with the Vancouver Island outbreak.

    Article  PubMed  CAS  Google Scholar 

  72. Bovers M, Hagen F, Kuramae EE, Boekhout T. Promiscuous mitochondria in Cryptococcus gattii. FEMS Yeast Res. 2009;9:489–503.

    Article  PubMed  CAS  Google Scholar 

  73. Litter J, Keszthelyi A, Hamari Z, Pfeiffer I, Kucsera J. Differences in mitochondrial genome organization of Cryptococcus neoformans strains. Antonie Van Leeuwenhoek. 2005;88:249–55.

    Article  PubMed  CAS  Google Scholar 

  74. • Xu J, Yan Z, Guo H. Divergence, hybridization, and recombination in the mitochondrial genome of the human pathogenic yeast Cryptococcus gattii. Mol Ecol. 2009;18:2628–42. Demonstrates historical mitochondrial genome divergence within C. gattii, with recent evidence for hybridization and recombination in the mitochondrial genome.

    Article  PubMed  CAS  Google Scholar 

  75. Kidd SE, Chow Y, Mak S, Bach PJ, Chen H, Hingston AO, et al. Characterization of environmental sources of the human and animal pathogen Cryptococcus gattii in British Columbia, Canada, and the Pacific Northwest of the United States. Appl Environ Microbiol. 2007;73:1433–43.

    Article  PubMed  CAS  Google Scholar 

  76. • Okamoto K, Hatakeyama S, Itoyama S, Nukui Y, Yoshino Y, Kitazawa T, et al. Cryptococcus gattii genotype VGIIa infection in man, Japan, 2007. Emerg Infect Dis. 2010;16:1155–7. First report of VGIIa outside of its previously described region of occurrence in the USA.

    Article  PubMed  Google Scholar 

  77. Saul N, Krockenberger M, Carter D. Evidence of recombination in mixed-mating type and alpha only populations of Cryptococcus gattii sourced from single eucalyptus tree hollows. Eukaryot Cell. 2008;7(4):727–34.

    Google Scholar 

  78. • Carriconde F, Gilgado F, Arthur I, Ellis D, Malik R, van de Wiele N, et al. Clonality and alpha-a recombination in the Australian Cryptococcus gattii VGII population – an emerging outbreak in Australia. PLoS One. 2011;6:e16936. Important analysis of the population genetics of VGII in Australia. Discusses and contrasts same-sex and opposite-sex hypotheses for the outbreak in the Pacific Northwest and Australia.

    Article  PubMed  CAS  Google Scholar 

  79. • Kidd SE, Bach PJ, Hingston AO, Mak S, Chow Y, MacDougall L, et al. Cryptococcus gattii dispersal mechanisms, British Columbia, Canada. Emerg Infect Dis. 2007;13:51–7. Important reference for the natural and human-driven dispersal mechanisms of C. gattii in the Pacific Northwest, with worldwide implications.

    Article  PubMed  Google Scholar 

  80. • Gillece JD, Schupp JM, Balajee SA, Harris J, Pearson T, Yan Y, et al. Whole genome sequence analysis of Cryptococcus gattii from the Pacific Northwest reveals unexpected diversity. PLoS One. 2011;6:e28550. Whole genome analysis of C. gattii drawing attention to similarities and differences between molecular types.

    Article  PubMed  CAS  Google Scholar 

  81. Callejas A, Ordonez N, Rodriguez MC, Castaneda E. First isolation of Cryptococcus neoformans var. gattii, serotype C, from the environment in Colombia. Med Mycol. 1998;36:341–4.

    PubMed  CAS  Google Scholar 

  82. Mseddi F, Sellami A, Jarboui MA, Sellami H, Makni F, Ayadi A. First environmental isolations of Cryptococcus neoformans and Cryptococcus gattii in Tunisia and review of published studies on environmental isolations in Africa. Mycopathologia. 2011;171:355–60.

    Article  PubMed  CAS  Google Scholar 

  83. Pfeiffer TJ, Ellis DH. Environmental isolation of Cryptococcus neoformans var. gattii from Eucalyptus tereticornis. Med Mycol. 1992;30:407–8.

    Article  CAS  Google Scholar 

  84. Randhawa HS, Kowshik T, Chowdhary A, Preeti Sinha K, Khan ZU, Sun S, et al. The expanding host tree species spectrum of Cryptococcus gattii and Cryptococcus neoformans and their isolations from surrounding soil in India. Med Mycol. 2008;46:1–11.

    Article  Google Scholar 

  85. • Litvintseva AP, Mitchell TG. Population genetic analyses reveal the African origin and strain variation of Cryptococcus neoformans var. grubii. PLoS Pathog. 2012;8:e1002495. A primary reference article revealing the ancestry and mode of transmission of the closely related species C. n. var. grubii. Important example of population genetics and analysis of diversity leading to insights into the geographic origin of a Cryptococcus species.

    Article  PubMed  CAS  Google Scholar 

  86. Romeo O, Scordino F, Chillemi V, Criseo G. Cryptococcus neoformans/Cryptococcus gattii species complex in southern Italy: an overview on the environmental diffusion of serotypes, genotypes and mating-types. Mycopathologia. 2012;174:283–91.

    Article  PubMed  Google Scholar 

  87. Iatta R, Hagen F, Fico C, Lopatriello N, Boekhout T, Montagna MT. Cryptococcus gattii Infection in an immunocompetent patient from Southern Italy. Mycopathologia. 2011;174:87–92.

    Article  PubMed  Google Scholar 

  88. • Viviani MA, Cogliati M, Esposto MC, Lemmer K, Tintelnot K, Colom Valiente MF, et al. Molecular analysis of 311 Cryptococcus neoformans isolates from a 30-month ECMM survey of cryptococcosis in Europe. FEMS Yeast Res. 2006;6:614–9. Demonstrates the presence of C. gattii cases in Europe, outside its typical tropical niche.

    Article  PubMed  CAS  Google Scholar 

  89. Chowdhary A, Rhandhawa HS, Prakash A, Meis JF. Environmental prevalence of Cryptococcus neoformans and Cryptococcus gattii in India: an update. Crit Rev Microbiol. 2012;38:1–16.

    Article  PubMed  Google Scholar 

  90. Chowdhary A, Hiremath SS, Sun S, Kowshik T, Randhawa HS, Xu J. Genetic differentiation, recombination and clonal expansion in environmental populations of Cryptococcus gattii in India. Environ Microbiol. 2011;13:1875–88.

    Article  PubMed  CAS  Google Scholar 

  91. Da Silva BK, Freire AK, Bentes Ados S, Sampaio Ide L, Santos LO, Dos Santos MS, et al. Characterization of clinical isolates of the Cryptococcus neoformans-Cryptococcus gattii species complex from the Amazonas State in Brazil. Rev Iberoam Micol. 2012;29:40–3.

    Article  PubMed  Google Scholar 

  92. Silva DC, Martins MA, Szeszs MW, Bonfietti LX, Matos D, Melhem MS. Susceptibility to antifungal agents and genotypes of Brazilian clinical and environmental Cryptococcus gattii strains. Diagn Microbiol Infect Dis. 2012;72:332–9.

    Article  PubMed  CAS  Google Scholar 

  93. Molez JF. The historical question of acquired immunodeficiency syndrome in the 1960s in the Congo River basin area in relation to cryptococcal meningitis. AmJTrop Med Hyg. 1998;58:273–6.

    CAS  Google Scholar 

  94. Swinne D, Nkurikiyinfura JB, Muyembe TL. Clinical isolates of Cryptococcus neoformans from Zaire. Eur J Clin Microbiol. 1986;5:50–1.

    Article  PubMed  CAS  Google Scholar 

  95. Kwon-Chung KJ, Bennett JE. High prevalence of Cryptococcus neoformans var. gattii in tropical and subtropical regions. Zentralbl Bakteriol Mikrobiol Hyg A. 1984;257:213–8.

    PubMed  CAS  Google Scholar 

  96. Lewden C, Salmon D, Morlat P, Bevilacqua S, Jougla E, Bonnet F, et al. Causes of death among human immunodeficiency virus (HIV)-infected adults in the era of potent antiretroviral therapy: emerging role of hepatitis and cancers, persistent role of AIDS. Int J Epidemiol. 2005;34:121–30.

    Article  PubMed  Google Scholar 

  97. • Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009;23:525–30. Important reference discussing the increasing incidence of cryptococcosis worldwide.

    Article  PubMed  Google Scholar 

  98. Mitchell TG, Perfect JR. Cryptococcosis in the era of AIDS – 100 years after the discovery of Cryptococcus neoformans. Clin Microbiol Rev. 1995;8:515–48.

    PubMed  CAS  Google Scholar 

  99. Khanna N, Chandramuki A, Desai A, Ravi V, Santosh V, Shankar SK, et al. Cryptococcosis in the immunocompromised host with special reference to AIDS. Indian J Chest Dis Allied Sci. 2000;42:311–5.

    PubMed  CAS  Google Scholar 

  100. Chaturvedi S, Dyavaiah M, Larsen RA, Chaturvedi V. Cryptococcus gattii in AIDS patients, southern California. Emerg Infect Dis. 2005;11:1686–92.

    Article  PubMed  CAS  Google Scholar 

  101. Chen S, Sorrell T, Nimmo G, Speed B, Currie B, Ellis D, et al. Epidemiology and host- and variety-dependent characteristics of infection due to Cryptococcus neoformans in Australia and New Zealand. Australasian Cryptococcal Study Group. Clin Infect Dis. 2000;31:499–508.

    Article  PubMed  CAS  Google Scholar 

  102. Karstaedt AS, Crewe-Brown HH, Dromer F. Cryptococcal meningitis caused by Cryptococcus neoformans var. gattii, serotype C, in AIDS patients in Soweto, South Africa. Med Mycol. 2002;40:7–11.

    PubMed  CAS  Google Scholar 

  103. Morgan J, McCarthy KM, Gould S, Fan K, Arthington-Skaggs B, Iqbal N, et al. Cryptococcus gattii infection: characteristics and epidemiology of cases identified in a South African province with high HIV seroprevalence, 2002–2004. Clin Infect Dis. 2006;43:1077–80.

    Article  PubMed  Google Scholar 

  104. Tay ST, Rohani MY, Soo Hoo TS, Hamimah H. Epidemiology of cryptococcosis in Malaysia. Mycoses. 2009;53:509–14.

    Article  Google Scholar 

  105. Bodasing N, Seaton RA, Shankland GS, Kennedy D. Cryptococcus neoformans var. gattii meningitis in an HIV-positive patient: first observation in the United Kingdom. J Infect. 2004;49:253–5.

    Article  PubMed  CAS  Google Scholar 

  106. Castanon-Olivares LR, Lopez-Martinez R, Barriga-Angulo G, Rios-Rosas C. Crytococcus neoformans var. gattii in an AIDS patient: first observation in Mexico. J Med Vet Mycol. 1997;35:57–9.

    Article  PubMed  CAS  Google Scholar 

  107. Castanon-Olivares LR, Arreguin-Espinosa R, y Santos Ruiz-Palacios G, Lopez-Martinez R. Frequency of Cryptococcus species and varieties in Mexico and their comparison with some Latin American countries. Rev Latinoam Microbiol. 2000;42:35–40.

    PubMed  CAS  Google Scholar 

  108. Bui T, Lin X, Malik R, Heitman J, Carter D. Isolates of Cryptococcus neoformans from infected animals reveal genetic exchange in unisexual, alpha mating type populations. Eukaryot Cell. 2008;7:1771–80.

    Article  PubMed  CAS  Google Scholar 

  109. •• Findley K, Sun S, Fraser JA, Hsueh YP, Averette AF, Li W, et al. Discovery of a modified tetrapolar sexual cycle in Cryptococcus amylolentus and the evolution of MAT in the Cryptococcus species complex. PLoS Genet. 2012;8:e1002528. A primary research article that describes the sexual cycle and sex determinants in nonpathogenic sister species of Cryptococcus. Fulfills a critical step in understanding of the evolution and plasticity of the sexual machinery in fungi.

    Article  PubMed  CAS  Google Scholar 

  110. Campbell LT, Fraser JA, Nichols CB, Dietrich FS, Carter D, Heitman J. Clinical and environmental isolates of Cryptococcus gattii from Australia that retain sexual fecundity. Eukaryot Cell. 2005;4:1410–9.

    Article  PubMed  CAS  Google Scholar 

  111. Chaturvedi V, Fan J, Stein B, Behr MJ, Samsonoff WA, Wickes BL, et al. Molecular genetic analyses of mating pheromones reveal intervariety mating or hybridization in Cryptococcus neoformans. Infect Immun. 2002;70:5225–35.

    Article  PubMed  CAS  Google Scholar 

  112. Carniato A, Scotton PG, Miotti AM, Mengoli C. Cryptococcus neoformans meningoencephalitis among apparently immunocompetent patients: description of two cases. Infez Med. 2009;17:41–5.

    PubMed  CAS  Google Scholar 

  113. Ma AL, Fong NC, Leung CW. Cryptococcal meningitis in an immunocompetent adolescent. Ann Trop Paediatr. 2008;28:231–4.

    Article  PubMed  CAS  Google Scholar 

  114. Kang Y, Tanaka H, Moretti ML, Mikami Y. New ITS genotype of Cryptococcus gattii isolated from an AIDS patient in Brazil. Microbiol Immunol. 2009;53:112–6.

    Article  PubMed  CAS  Google Scholar 

  115. Kozubowski L, Heitman J. Profiling a killer, the development of Cryptococcus neoformans. FEMS Microbiol Rev. 2012;36:78–94.

    Article  PubMed  CAS  Google Scholar 

  116. Lester SJ, Malik R, Bartlett KH, Duncan CG. Cryptococcosis: update and emergence of Cryptococcus gattii. Vet Clin Pathol. 2011;40:4–17.

    Article  PubMed  Google Scholar 

  117. Kwon-Chung KJ, Edman JC, Wickes BL. Genetic association of mating types and virulence in Cryptococcus neoformans. Infect Immun. 1992;60:602–5.

    PubMed  CAS  Google Scholar 

  118. Wickes BL. The role of mating type and morphology in Cryptococcus neoformans pathogenesis. Int J Med Microbiol. 2002;292:313–29.

    Article  PubMed  CAS  Google Scholar 

  119. Nielsen K, Cox GM, Wang P, Toffaletti DL, Perfect JR, Heitman J. Sexual cycle of Cryptococcus neoformans var. grubii and virulence of congenic a and a Isolates. Infect Immun. 2003;71:4831–41.

    Article  PubMed  CAS  Google Scholar 

  120. Toffaletti DL, Nielsen K, Dietrich F, Heitman J, Perfect JR. Cryptococcus neoformans mitochondrial genomes from serotype A and D strains do not influence virulence. Curr Genet. 2004;46:193–204.

    Article  PubMed  CAS  Google Scholar 

  121. Nielsen K, Marra RE, Hagen F, Boekhout T, Mitchell TG, Cox GM, et al. Interaction between genetic background and the mating-type locus in Cryptococcus neoformans virulence potential. Genetics. 2005;171:975–83.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Jo Kingsbury, Anna Averette, Marianna Feretzaki, and Virginia Lehman for critical review of the manuscript. This research was supported by R37 award AI39115 and RO1 award AI50113 from the NIH/NIAID.

Disclosure

D.J. Springer: none; S. Phadke: none; R. Billmyer: grant from the NIH; J. Heitman: employed by Duke, grants from NIH, Merck and Astellas

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Springer, D.J., Phadke, S., Billmyre, R.B. et al. Cryptococcus gattii, No Longer an Accidental Pathogen?. Curr Fungal Infect Rep 6, 245–256 (2012). https://doi.org/10.1007/s12281-012-0111-0

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