Phenotypic switching has been described in serotype A and D strains of Cryptococcus neoformans. It occurs in vivo during chronic infection and is associated with differential gene expression and changes in virulence. The switch involves changes in the polysaccharide capsule and cell wall that affect the yeast's ability to resist phagocytosis. In addition, the phenotypic switch variants elicit qualitatively different inflammatory responses in the host. In animal models of chronic cryptococosis, the immune response of the host ultimately determines which of the switch variants are selected and maintained. The importance of phenotypic switching is further underscored by several findings that are relevant in the setting of human disease. These include the ability of the mucoid colony variant of RC-2 (RC-2 MC) but not the smooth variant (RC-2 SM) to promote increased intracerebral pressure in a rat model of cryptococcal meningitis. Furthermore, chemotherapeutic and immunological antifungal interventions can promote the selection of the RC-2 MC variant during chronic murine infection.
BrandtM. E, PfallerM. A, HajjehR. A, GravissE. A, ReesJ, SpitzerE. D, PinnerR. W, MayerL. W.
1996; Molecular subtypes and antifungal susceptibilities of serial Cryptococcus neoformans isolates in human immunodeficiency virus-associated cryptococcosis. Cryptococcal Disease Active Surveillance Group. J Infect Dis 174:812–820[CrossRef]
BrandtM. E, PfallerM. A, HajjehR. A, HamillR. J, PappasP. G, ReingoldA. L, RimlandD, WarnockD. W.
2001; Trends in antifungal drug susceptibility of Cryptococcus neoformans isolates in the United States: 1992 to 1994 and 1996 to 1998. Antimicrob Agents Chemother 45:3065–3069[CrossRef]
CherniakR, MorrisL. C, BelayT, SpitzerE. D, CasadevallA.
1995; Variation in the structure of glucuronoxylomannan in isolates from patients with recurrent cryptococcal meningitis. Infect Immun 63:1899–1905
CherniakR, ValafarH, MorrisL, ValafarF.
1998; Cryptococcus neoformans chemotyping by quantitative analysis of [sup]1[/sup]H nuclear magnetic resonance spectra of glucuronoxylomannans with a computer-simulated artificial neural network. Clin Diagn Lab Immunol 5:146–159
CurrieB, SanatiH, IbrahimA. S, GhannoumM. A,
EdwardsJ. E., Jr,
CasadevallA. 1995; Sterol compositions and susceptibilities to amphotericin B of environmental Cryptococcus neoformans isolates are changed by murine passage. Antimicrob Agents Chemother 39:1934–1937[CrossRef]
DeitschK. W, MoxonE. R, WellemsT. E.
1997; Shared themes of antigenic variation and virulence in bacterial, protozoal, and fungal infections. Microbiol Mol Biol Rev 61:281–293
D'SouzaC. A, HeitmanJ.
2001; It infects me, it infects me not: phenotypic switching in the fungal pathogen Cryptococcus neoformans . J Clin Invest 108:1577–1578[CrossRef]
EissenbergL. G, PoirierS, GoldmanW. E.
1996; Phenotypic variation and persistence of Histoplasma capsulatum yeasts in host cells. Infect Immun 64:5310–5314
FeldmesserM, KressY, CasadevallA.
2001; Dynamic changes in the morphology of Cryptococcus neoformans during murine pulmonary infection. Microbiology 147:2355–2365
FranzotS, MukherjeeJ, CherniakR, ChenL, HamdanJ, CasadevallA.
1998; Microevolution of a standard strain of Cryptococcus neoformans resulting in differences in virulence and other phenotypes. Infect Immun 66:89–97
FriesB. C, CasadevallA.
1998; Serial isolates of Cryptococcus neoformans from patients with AIDS differ in virulence for mice. J Infect Dis 178:1761–1766[CrossRef]
FriesB. C, TabordaC. P, SerfassE, CasadevallA.
2001; Phenotypic switching of Cryptococcus neoformans occurs in vivo and influences the outcome of infection. J Clin Invest 108:1639–1648[CrossRef]
FriesB. C, CookE, WangX, CasadevallA.
2005a; Effects of antifungal interventions on the outcome of experimental infections with phenotypic switch variants of Cryptococcus neoformans . Antimicrob Agents Chemother 49:350–357[CrossRef]
FriesB. C, LeeS. C, KennanR, ZhaoW, CasadevallA, GoldmanD. L.
2005b; Phenotypic switching of Cryptococcus neoformans can produce variants that elicit increased intracranial pressure in a rat model of cryptococcal meningoencephalitis. Infect Immun 73:1779–1787[CrossRef]
GoldmanD, FriesB, FranzotS, MontellaL, CasadevallA.
1998; Phenotypic switching in the human pathogenic fungus Cryptococcus neoformans is associated with changes in virulence and pulmonary inflammatory response in rodents. Proc Natl Acad Sci U S A 95:14967–14972[CrossRef]
GuerreroA, JainN, CookE, CasadevallA, FriesB.
2003; Phenotypic switch variants of Cryptococcus neoformans differ in gene expression profile. In 103rd General Meeting of the American Society for Microbiology Washington DC: Abstract F39
KlarA. J, SrikanthaT, SollD. R.
2001; A histone deacetylation inhibitor and mutant promote colony-type switching of the human pathogen Candida albicans . Genetics 158:919–924
KuglerS, Schurtz SebghatiT, Groppe EissenbergL, GoldmanW. E.
2000; Phenotypic variation and intracellular parasitism by Histoplasma capsulatum . Proc Natl Acad Sci U S A 97:8794–8798[CrossRef]
LachkeS. A, SrikanthaT, TsaiL. K, DanielsK, SollD. R.
2000; Phenotypic switching in Candida glabrata involves phase-specific regulation of the metallothionein gene MT-II and the newly discovered hemolysin gene HLP. Infect Immun 68:884–895[CrossRef]
LevitzS. M, NongS. H, SeetooK. F, HarrisonT. S, SpeizerR. A, SimonsE. R.
1999; Cryptococcus neoformans resides in an acidic phagolysosome of human macrophages. Infect Immun 67:885–890
MillerM. G, JohnsonA. D.
2002; White-opaque switching in Candida albicans is controlled by mating-type locus homeodomain proteins and allows efficient mating. Cell 110:293–302[CrossRef]
MirzaS. A, PhelanM, RimlandD. 8 other authors2003; The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992–2000. Clin Infect Dis 36:789–794[CrossRef]
MylerP, AllisonJ, AgabianN, StuartK.
1984; Antigenic variation in African trypanosomes by gene replacement or activation of alternate telomeres. Cell 39:203–211[CrossRef]
PfallerM. A, ZhangJ, MesserS. A, BrandtM. E, HajjehR. A, JessupC. J, TumberlandM, MbiddeE. K, GhannoumM. A.
1999; In vitro activities of voriconazole, fluconazole, and itraconazole against 566 clinical isolates of Cryptococcus neoformans from the United States and Africa. Antimicrob Agents Chemother 43:169–171[CrossRef]
PietrellaD, FriesB, LupoP, BistoniF, CasadevallA, VecchiarelliA.
2003; Phenotypic switching of Cryptococcus neoformans can influence the outcome of the human immune response. Cell Microbiol 5:513–522[CrossRef]
RadfordD, ChallacombeS, WalterJ.
1994; A scanning electron microscopy investigation of the structure of colonies of different morphologies produced by phenotypic switching in Candida albicans . J Med Microbiol 40:416–423[CrossRef]
SilvermanM, ZiegJ, HilmenM, SimonM.
1979; Phase variation in Salmonella : genetic analysis of a recombinational switch. Proc Natl Acad Sci U S A 76:391–395[CrossRef]
SlutskyB, StaebellM, AndersonJ, RisenL, PfallerM, SollD. R.
1987; “White-opaque transition”: a second high-frequency switching system in Candida albicans . J Bacteriol 169:189–197
SrikanthaT, TsaiL, DanielsK, KlarA. J, SollD. R.
2001; The histone deacetylase genes HDA1 and RPD3 play distinct roles in regulation of high-frequency phenotypic switching in Candida albicans . J Bacteriol 183:4614–4625[CrossRef]
SteenbergenJ. N, ShumanH. A, CasadevallA.
2001; Cryptococcus neoformans interactions with amoebae suggest an explanation for its virulence and intracellular pathogenic strategy in macrophages. Proc Natl Acad Sci U S A 98:15245–15250[CrossRef]
VargasK, MesserS. A, PfallerM, LockhartS. R, StapletonJ. T, HellsteinJ, SollD. R.
2000; Elevated phenotypic switching and drug resistance of Candida albicans from human immunodeficiency virus-positive individuals prior to first thrush episode. J Clin Microbiol 38:3595–3607