Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis
- Sharon Chen, PhD, MBBS, FRACP, FRCPA
Sharon Chen, PhD, MBBS, FRACP, FRCPA
- Clinical Associate Professor
- Sydney Medical School, University of Sydney
- Kieren A Marr, MD
Kieren A Marr, MD
- Section Editor — Compromised Host Infections; Fungal Infections
- Professor of Medicine and Oncology
- Johns Hopkins University School of Medicine
- Tania C Sorrell, MD
Tania C Sorrell, MD
- Professor of Clinical Infectious Diseases and Director of the Centre for Infectious Diseases and Microbiology
- Sydney Medical School, University of Sydney
Cryptococcus gattii is a fungal pathogen that is endemic in the tropics and subtropics and that has also caused an outbreak that is ongoing in British Columbia, Canada, and the United States Pacific Northwest; C. gattii is genetically and biochemically distinct from Cryptococcus neoformans [1-3]. Together, C. gattii and C. neoformans account for most cases of cryptococcal infections in humans, although C. neoformans is more common. Like C. neoformans, infection with C. gattii manifests most often as meningoencephalitis and/or pneumonia.
The microbiology, epidemiology, risk factors, and pathogenesis of C. gattii infection will be reviewed here. The clinical features, diagnosis, and treatment of C. gattii infection are discussed separately. C. neoformans infection is also reviewed elsewhere. (See "Cryptococcus gattii infection: Clinical features and diagnosis" and "Cryptococcus gattii infection: Treatment" and "Microbiology and epidemiology of Cryptococcus neoformans infection" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-infected patients" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-seronegative patients".)
C. gattii is a basidiomycetous fungus, which can be found in the environment (see 'Environmental exposure' below). In clinical specimens, C. gattii is visualized as single or budding yeasts with round to cylindrical cells enveloped in a thick polysaccharide capsule. It was first proposed as a new taxonomic entity, Cryptococcus neoformans var gattii, in 1970 , in parallel with the characterization of the capsular antigens of C. neoformans. It is now characterized as a separate species, C. gattii.
Of the four major capsular serotypes of Cryptococcus spp (A, B, C, and D), B and C serotypes are exclusive to what has become known as C. gattii, a species distinct from C. neoformans [5,6]. Recognition of rare hybrids of C. gattii and C. neoformans provide evidence of taxonomic proximity, but not identity, between the two species [7,8].
Microbiologic tests used for the diagnosis of C. gattii infection are discussed separately. (See "Cryptococcus gattii infection: Clinical features and diagnosis", section on 'Culture and histopathology'.)
- Sorrell TC. Cryptococcus neoformans variety gattii. Med Mycol 2001; 39:155.
- Chaturvedi V, Chaturvedi S. Cryptococcus gattii: a resurgent fungal pathogen. Trends Microbiol 2011; 19:564.
- Harris J, Lockhart S, Chiller T. Cryptococcus gattii: where do we go from here? Med Mycol 2012; 50:113.
- Gatti F, Eeckels R. An atypical strain of Cryptococcus neoformans (San Felice) Vuillemin 1894. I. Description of the disease and of the strain. Ann Soc Belges Med Trop Parasitol Mycol 1970; 50:689.
- Kwon-Chung KJ, Boekhout T, Fell JW, Diaz M. Proposal to conserve the name Cryptococcus gattii against C. hondurianus and C. bacillisporus (Basidiomycota, Hymenomycetes, Tremellomycetiadae). Taxon 2002; 51:804.
- Sharpton TJ, Neafsey DE, Galagan JE, Taylor JW. Mechanisms of intron gain and loss in Cryptococcus. Genome Biol 2008; 9:R24.
- Bovers M, Hagen F, Kuramae EE, et al. AIDS patient death caused by novel Cryptococcus neoformans x C. gattii hybrid. Emerg Infect Dis 2008; 14:1105.
- Chen SC, Meyer W, Sorrell TC. Cryptococcus gattii infections. Clin Microbiol Rev 2014; 27:980.
- Meyer W. Cryptococcus gattii in the Age of Whole-Genome Sequencing. MBio 2015; 6:e01761.
- Meyer W, Aanensen DM, Boekhout T, et al. Consensus multi-locus sequence typing scheme for Cryptococcus neoformans and Cryptococcus gattii. Med Mycol 2009; 47:561.
- Bovers M, Hagen F, Kuramae EE, Boekhout T. Six monophyletic lineages identified within Cryptococcus neoformans and Cryptococcus gattii by multi-locus sequence typing. Fungal Genet Biol 2008; 45:400.
- Sidrim JJ, Costa AK, Cordeiro RA, et al. Molecular methods for the diagnosis and characterization of Cryptococcus: a review. Can J Microbiol 2010; 56:445.
- Hagen F, Khayhan K, Theelen B, et al. Recognition of seven species in the Cryptococcus gattii/Cryptococcus neoformans species complex. Fungal Genet Biol 2015; 78:16.
- Kwon-Chung KJ, Bennett JE, Wickes BL, et al. The Case for Adopting the "Species Complex" Nomenclature for the Etiologic Agents of Cryptococcosis. mSphere 2017; 2.
- Meyer W, Gilgado F, Ngamskulrungroj P, et al. Molecular typing of the Cryptococcus neoformans/Cryptococcus gattii species complex. In: Cryptococcus: from pathogen to model yeast, Heitman J, Kozel TR, Kwon-Chung J, Perfect J, Casadevall A (Eds) (Eds), ASM Press, Washington DC 2011. p.327.
- Byrnes EJ 3rd, Bartlett KH, Perfect JR, Heitman J. Cryptococcus gattii: an emerging fungal pathogen infecting humans and animals. Microbes Infect 2011; 13:895.
- Campbell LT, Fraser JA, Nichols CB, et al. Clinical and environmental isolates of Cryptococcus gattii from Australia that retain sexual fecundity. Eukaryot Cell 2005; 4:1410.
- Chen SC, Currie BJ, Campbell HM, et al. Cryptococcus neoformans var. gattii infection in northern Australia: existence of an environmental source other than known host eucalypts. Trans R Soc Trop Med Hyg 1997; 91:547.
- Kidd SE, Hagen F, Tscharke RL, 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.
- Byrnes EJ 3rd, Bildfell RJ, Frank SA, et al. 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.
- 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.
- Nyazika TK, Hagen F, Meis JF, Robertson VJ. Cryptococcus tetragattii as a major cause of cryptococcal meningitis among HIV-infected individuals in Harare, Zimbabwe. J Infect 2016; 72:745.
- Mitchell DH, Sorrell TC, Allworth AM, et al. Cryptococcal disease of the CNS in immunocompetent hosts: influence of cryptococcal variety on clinical manifestations and outcome. Clin Infect Dis 1995; 20:611.
- Speed B, Dunt D. Clinical and host differences between infections with the two varieties of Cryptococcus neoformans. Clin Infect Dis 1995; 21:28.
- Chen S, Sorrell T, Nimmo G, 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.
- MacDougall L, Kidd SE, Galanis E, et al. Spread of Cryptococcus gattii in British Columbia, Canada, and detection in the Pacific Northwest, USA. Emerg Infect Dis 2007; 13:42.
- Galanis E, Macdougall L, Kidd S, et al. Epidemiology of Cryptococcus gattii, British Columbia, Canada, 1999-2007. Emerg Infect Dis 2010; 16:251.
- Datta K, Bartlett KH, Baer R, et al. Spread of Cryptococcus gattii into Pacific Northwest region of the United States. Emerg Infect Dis 2009; 15:1185.
- Centers for Disease Control and Prevention (CDC). Emergence of Cryptococcus gattii-- Pacific Northwest, 2004-2010. MMWR Morb Mortal Wkly Rep 2010; 59:865.
- Marr KA. Cryptococcus gattii as an important fungal pathogen of western North America. Expert Rev Anti Infect Ther 2012; 10:637.
- Harris JR, Lockhart SR, Debess E, et al. Cryptococcus gattii in the United States: clinical aspects of infection with an emerging pathogen. Clin Infect Dis 2011; 53:1188.
- Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis 2010; 50:291.
- Phillips P, Galanis E, MacDougall L, et al. Longitudinal clinical findings and outcome among patients with Cryptococcus gattii infection in British Columbia. Clin Infect Dis 2015; 60:1368.
- Stephen C, Lester S, Black W, et al. Multispecies outbreak of cryptococcosis on southern Vancouver Island, British Columbia. Can Vet J 2002; 43:792.
- Hoang LM, Maguire JA, Doyle P, et al. Cryptococcus neoformans infections at Vancouver Hospital and Health Sciences Centre (1997-2002): epidemiology, microbiology and histopathology. J Med Microbiol 2004; 53:935.
- Bartlett KH, Kidd SE, Kronstad JW. The emergence of Cryptococcus gattii in British Columbia and the Pacific Northwest. Curr Infect Dis Rep 2008; 10:58.
- BC Centre for Disease Control. 2015 British Columbia annual summary of reportable diseases. http://www.bccdc.ca/resource-gallery/Documents/Statistics%20and%20Research/Statistics%20and%20Reports/Epid/Annual%20Reports/2015CDAnnualReportFinal.pdf (Accessed on May 17, 2017).
- Kunadharaju R, Choe U, Harris JR, et al. Cryptococcus gattii, Florida, USA, 2011. Emerg Infect Dis 2013; 19:519.
- Harris JR, Lockhart SR, Sondermeyer G, et al. Cryptococcus gattii infections in multiple states outside the US Pacific Northwest. Emerg Infect Dis 2013; 19:1620.
- Chowdhary A, Randhawa HS, Boekhout T, et al. Temperate climate niche for Cryptococcus gattii in Northern Europe. Emerg Infect Dis 2012; 18:172.
- Montagna MT, Viviani MA, Pulito A. Cryptococcus neoformans var. gattii in Italy. Environmental investigation related to an autochtonous clinical case in Apulia. J Mycol Med 1997; 7:93.
- Hagen F, Hare Jensen R, Meis JF, Arendrup MC. Molecular epidemiology and in vitro antifungal susceptibility testing of 108 clinical Cryptococcus neoformans sensu lato and Cryptococcus gattii sensu lato isolates from Denmark. Mycoses 2016; 59:576.
- Herkert PF, Hagen F, de Oliveira Salvador GL, et al. Molecular characterisation and antifungal susceptibility of clinical Cryptococcus deuterogattii (AFLP6/VGII) isolates from Southern Brazil. Eur J Clin Microbiol Infect Dis 2016; 35:1803.
- Kwon-Chung KJ, Bennett JE. Epidemiologic differences between the two varieties of Cryptococcus neoformans. Am J Epidemiol 1984; 120:123.
- Morgan J, McCarthy KM, Gould S, 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.
- Ellis DH, Pfeiffer TJ. Natural habitat of Cryptococcus neoformans var. gattii. J Clin Microbiol 1990; 28:1642.
- Ellis D, Pfeiffer T. Cryptococcosis and the ecology of Cryptococcus neoformans. Jpn J Med Mycol 1995; 35:111.
- Sorrell TC, Chen SC, Ruma P, et al. Concordance of clinical and environmental isolates of Cryptococcus neoformans var. gattii by random amplification of polymorphic DNA analysis and PCR fingerprinting. J Clin Microbiol 1996; 34:1253.
- Chen SC, Slavin MA, Heath CH, et al. Clinical manifestations of Cryptococcus gattii infection: determinants of neurological sequelae and death. Clin Infect Dis 2012; 55:789.
- Montenegro H, Paula CR. Environmental isolation of Cryptococcus neoformans var. gattii and C. neoformans var. neoformans in the city of São Paulo, Brazil. Med Mycol 2000; 38:385.
- Keah KC, Parameswari S, Cheong YM. Serotypes of clinical isolates of Cryptococcus neoformans in Malaysia. Trop Biomed 1994; 11:205.
- Cogliati M, D'Amicis R, Zani A, et al. Environmental distribution of Cryptococcus neoformans and C. gattii around the Mediterranean basin. FEMS Yeast Res 2016; 16.
- Springer DJ, Billmyre RB, Filler EE, et al. Cryptococcus gattii VGIII isolates causing infections in HIV/AIDS patients in Southern California: identification of the local environmental source as arboreal. PLoS Pathog 2014; 10:e1004285.
- Marr KA, Datta K, Pirofski LA, Barnes R. Cryptococcus gattii infection in healthy hosts: a sentinel for subclinical immunodeficiency? Clin Infect Dis 2012; 54:153.
- Lalloo D, Fisher D, Naraqi S, et al. Cryptococcal meningitis (C. neoformans var. gattii) leading to blindness in previously healthy Melanesian adults in Papua New Guinea. Q J Med 1994; 87:343.
- Jenney A, Pandithage K, Fisher DA, Currie BJ. Cryptococcus infection in tropical Australia. J Clin Microbiol 2004; 42:3865.
- MacDougall L, Fyfe M, Romney M, et al. Risk factors for Cryptococcus gattii infection, British Columbia, Canada. Emerg Infect Dis 2011; 17:193.
- Chaturvedi S, Dyavaiah M, Larsen RA, Chaturvedi V. Cryptococcus gattii in AIDS patients, southern California. Emerg Infect Dis 2005; 11:1686.
- Forrest GN, Bhalla P, DeBess EE, et al. Cryptococcus gattii infection in solid organ transplant recipients: description of Oregon outbreak cases. Transpl Infect Dis 2015; 17:467.
- Zonios DI, Falloon J, Huang CY, et al. Cryptococcosis and idiopathic CD4 lymphocytopenia. Medicine (Baltimore) 2007; 86:78.
- Netea MG, Brouwer AE, Hoogendoorn EH, et al. Two patients with cryptococcal meningitis and idiopathic CD4 lymphopenia: defective cytokine production and reversal by recombinant interferon- gamma therapy. Clin Infect Dis 2004; 39:e83.
- Hamann ID, Gillespie RJ, Ferguson JK. Primary cryptococcal cellulitis caused by Cryptococcus neoformans var. gattii in an immunocompetent host. Australas J Dermatol 1997; 38:29.
- Chen SC, Muller M, Zhou JZ, et al. Phospholipase activity in Cryptococcus neoformans: a new virulence factor? J Infect Dis 1997; 175:414.
- Casadevall A, Perfect JR. Animal models and veterinary aspects of cryptococcosis. In: Cryptococcosis, ASM Press, Washington DC 1998. p.325.
- Leopold Wager CM, Hole CR, Wozniak KL, Wormley FL Jr. Cryptococcus and Phagocytes: Complex Interactions that Influence Disease Outcome. Front Microbiol 2016; 7:105.
- Ngamskulrungroj P, Price J, Sorrell T, et al. Cryptococcus gattii virulence composite: candidate genes revealed by microarray analysis of high and less virulent Vancouver island outbreak strains. PLoS One 2011; 6:e16076.
- Schoffelen T, Illnait-Zaragozi MT, Joosten LA, et al. Cryptococcus gattii induces a cytokine pattern that is distinct from other cryptococcal species. PLoS One 2013; 8:e55579.
- Saijo T, Chen J, Chen SC, et al. Anti-granulocyte-macrophage colony-stimulating factor autoantibodies are a risk factor for central nervous system infection by Cryptococcus gattii in otherwise immunocompetent patients. MBio 2014; 5:e00912.
- Chaturvedi S, Chaturvedi V. Virulence mechanisms of Cryptococcus gattii: Convergence and divergence. In: Cryptococcus: From Human Pathogen to Model Yeast, Heitman J, Kozel T, Kwon-Chung KJ, et al. (Eds), ASM Press, Washington, DC 2011.
- Noverr MC, Williamson PR, Fajardo RS, Huffnagle GB. CNLAC1 is required for extrapulmonary dissemination of Cryptococcus neoformans but not pulmonary persistence. Infect Immun 2004; 72:1693.
- Santangelo R, Zoellner H, Sorrell T, et al. Role of extracellular phospholipases and mononuclear phagocytes in dissemination of cryptococcosis in a murine model. Infect Immun 2004; 72:2229.
- Shi M, Li SS, Zheng C, et al. Real-time imaging of trapping and urease-dependent transmigration of Cryptococcus neoformans in mouse brain. J Clin Invest 2010; 120:1683.
- Charlier C, Nielsen K, Daou S, et al. Evidence of a role for monocytes in dissemination and brain invasion by Cryptococcus neoformans. Infect Immun 2009; 77:120.
- Ma H, Croudace JE, Lammas DA, May RC. Expulsion of live pathogenic yeast by macrophages. Curr Biol 2006; 16:2156.
- Oliveira DL, Freire-de-Lima CG, Nosanchuk JD, et al. Extracellular vesicles from Cryptococcus neoformans modulate macrophage functions. Infect Immun 2010; 78:1601.
- Wang H, Sun J, Goldstein H. Human immunodeficiency virus type 1 infection increases the in vivo capacity of peripheral monocytes to cross the blood-brain barrier into the brain and the in vivo sensitivity of the blood-brain barrier to disruption by lipopolysaccharide. J Virol 2008; 82:7591.
- Krockenberger MB, Malik R, Ngamskulrungroj P, et al. Pathogenesis of pulmonary Cryptococcus gattii infection: a rat model. Mycopathologia 2010; 170:315.