Key Points
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Cryptococcus neoformans is generally considered to be an opportunistic pathogen because of its tendency to infect immunocompromised individuals. However, this view has been challenged by recent discoveries of specialized interactions between the fungus and its mammalian hosts, and by the emergence of the related species Cryptococcus gattii as a primary pathogen of immunocompetent populations.
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Methods have been developed to separate the yeast cells (4–10 μm) from the spores (1–2 μm in diameter) that result from sexual development and meiosis in C. neoformans. The spores are infectious, as has long been suspected, and they are readily phagocytosed by macrophages in the absence of an opsonin, whereas yeast cells require prior opsonization.
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C. neoformans and C. gattii disseminate from the lung and cross the blood–brain barrier (BBB) to cause meningoencephalitis. The fungal cells cross the BBB directly by transcytosis through endothelial cells lining vessels in the brain, and by a 'Trojan Horse' strategy that involves transport in phagocytic cells.
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Intracellular cryptococcal cells residing in phagosomes can escape their phagocytic host cells by expulsion and by cell-to-cell transfer between macrophages. Cycles of actin polymerization (actin 'flashes') seem to form transient cages around phagosomes, potentially providing a barrier to expulsion.
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C. gattii has emerged as a pathogen of immunocompetent humans and animals in western North America. The associated C. gattii strains appear to have a high intracellular proliferation rate in macrophages, and this is correlated with their virulence; they also trigger a reduced protective inflammatory response compared with the response triggered by a representative C. neoformans strain.
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Giant cells (up to 100 μm) account for ∼20% of the cryptococcal burden during lung infection. These cells are polyploid and resistant to phagocytosis.
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Studies with fresh isolates of C. neoformans from patients with AIDS revealed that mixed infections, as well as changes in ploidy resulting from endoreplication, are more common during cryptococcosis than previously thought. In addition, clinical isolates and strains that display antifungal-drug resistance can harbour disomic chromosomes.
Abstract
Cryptococcus neoformans is generally considered to be an opportunistic fungal pathogen because of its tendency to infect immunocompromised individuals, particularly those infected with HIV. However, this view has been challenged by the recent discovery of specialized interactions between the fungus and its mammalian hosts, and by the emergence of the related species Cryptococcus gattii as a primary pathogen of immunocompetent populations. In this Review, we highlight features of cryptococcal pathogens that reveal their adaptation to the mammalian environment. These features include not only remarkably sophisticated interactions with phagocytic cells to promote intracellular survival, dissemination to the central nervous system and escape, but also surprising morphological and genomic adaptations such as the formation of polyploid giant cells in the lung.
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References
Brizendine, K. D. & Pappas, P. G. Cryptococcal meningitis: Current approaches to management in patients with and without AIDS. Curr. Infect. Dis. Rep. 12, 299–305 (2010).
Park, B. J. et al. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 23, 525–30 (2009). This study provides the first global view of the burden of cryptococcosis and reveals that there are ∼1 million cases per year, resulting in ∼625,000 deaths. The highest burden is in sub-Saharan Africa.
Bartlett, K. H., Kidd, S. E. & Kronstad, J. W. The emergence of Cryptococcus gattii in British Columbia and the Pacific Northwest. Curr. Infect. Dis. Rep. 10, 58–65 (2008).
Byrnes, E. J. 3rd 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. 199, 1081–1086 (2009).
Byrnes, E. J. 3rd et al. Emergence and pathogenicity of highly virulent Cryptococcus gattii genotypes in the northwest United States. PLoS Pathog. 6, e1000850 (2010).
Datta, K. et al. Spread of Cryptococcus gattii into Pacific Northwest region of the United States. Emerg. Infect. Dis. 15, 1185–1191 (2009).
Galanis, E. & Macdougall, L. Epidemiology of Cryptococcus gattii, British Columbia, Canada, 1999–2007. Emerg. Infect. Dis. 16, 251–257 (2010).
Kwon-Chung, K. J., Boekhout, T., Fell, J. W. & Diaz, M. Proposal to conserve the name Cryptococcus gattii against C. hondurianus and C. bacillisporus (Basidiomycota, Hymenomycetes, Tremellomycetidae). Taxon 51, 804–806 (2002).
Mitchell, T. G. & Perfect, J. R. Cryptococcosis in the era of AIDS—100 years after the discovery of Cryptococcus neoformans. Clin. Microbiol. Rev. 8, 515–548 (1995).
Sorrell, T. C. Cryptococcus neoformans variety gattii. Med. Mycol. 39, 155–168 (2001).
Casadevall, A., Nosanchuk, J. D., Williamson, P. & Rodrigues, M. L. Vesicular transport across the fungal cell wall. Trends Microbiol. 17, 158–162 (2009).
Casadevall, A. & Pirofski, L. A. The damage-response framework of microbial pathogenesis. Nature Rev. Microbiol. 1, 17–24 (2003).
Idnurm, A. et al. Deciphering the model pathogenic fungus Cryptococcus neoformans. Nature Rev. Microbiol. 3, 753–764 (2005).
Jung, W. H. & Kronstad, J. W. Iron and fungal pathogenesis: a case study with Cryptococcus neoformans. Cell. Microbiol. 10, 277–284 (2008).
Doering, T. L. How sweet it is! Cell wall biogenesis and polysaccharide capsule formation in Cryptococcus neoformans. Annu. Rev. Microbiol. 63, 223–247 (2009).
Kozubowski, L., Lee, S. C. & Heitman, J. Signalling pathways in the pathogenesis of Cryptococcus. Cell. Microbiol. 11, 370–380 (2009).
Lin, X. Cryptococcus neoformans: morphogenesis, infection, and evolution. Infect. Genet. Evol. 9, 401–416 (2009).
Ma, H. & May, R. C. Virulence in Cryptococcus species. Adv. Appl. Microbiol. 67, 131–190 (2009).
Zaragoza, O. et al. The capsule of the fungal pathogen Cryptococcus neoformans. Adv. Appl. Microbiol. 68, 133–216 (2009).
Voelz, K. & May, R. C. Cryptococcal interactions with the host immune system. Eukaryot. Cell 9, 835–846 (2010).
Casadevall, A. & Perfect, J. R. Cryptococcus neoformans (American Society for Microbiology Press, Washington DC, 1998).
Heitman, J., Kozel, T. R., Kwon-Chung, K. J., Perfect, J. R. & Casadevall, A. (eds) Cryptococcus: From Human Pathogen to Model Yeast (American Society for Microbiology Press, Washington DC, 2010).
Lin, X, Hull, C. M. & Heitman J. Sexual reproduction between partners of the same mating type in Cryptococcus neoformans. Nature 434, 1017–1021 (2005).
Botts, M. R., Giles, S. S., Gates, M. A., Kozel, T. R. & Hull, C. M. Isolation and characterization of Cryptococcus neoformans spores reveal a critical role for capsule biosynthesis genes in spore biogenesis. Eukaryot. Cell 8, 595–605 (2009).
Xue, C., Tada, Y., Dong, X. & Heitman, J. The human fungal pathogen Cryptococcus can complete its sexual cycle during a pathogenic association with plants. Cell Host Microbe 1, 263–273 (2007).
Velagapudi, R., Hsueh, Y. P., Geunes-Boyer, S., Wright, J. R. & Heitman, J. Spores as infectious propagules of Cryptococcus neoformans. Infect. Immun. 77, 4345–4355 (2009). This article and reference 24 describe the development of methods to isolate and characterize cryptococcal spores.
Vartivarian, S. E. et al. Regulation of cryptococcal capsular polysaccharide by iron. J. Infect. Dis. 167, 186–190 (1993).
Giles, S. S., Dagenais, T. R., Botts, M. R., Keller, N. P. & Hull, C. M. Elucidating the pathogenesis of spores from the human fungal pathogen Cryptococcus neoformans. Infect. Immun. 77, 3491–3500 (2009). This article and reference 26 provide evidence that cryptococcal spores are infectious agents, and analyse the interactions of spores with phagocytic cells. This article also describes initial studies of spore surface molecules such as β-(1,3)-glucan, and of macrophage receptors such as dectin 1.
Feldmesser, M., Kress, Y., Novikoff, P. & Casadevall, A. Cryptococcus neoformans is a facultative intracellular pathogen in murine pulmonary infection. Infect. Immun. 68, 4225–4237 (2000).
Botts, M. R. & Hull, C. M. Dueling in the lung: how Cryptococcus spores race the host for survival. Curr. Opin. Microbiol. 13, 437–442 (2010).
Chang, Y. C. et al. Cryptococcal yeast cells invade the central nervous system via transcellular penetration of the blood-brain barrier. Infect. Immun. 72, 4985–4995 (2004).
Shea, J. M., Kechichian, T. B., Luberto, C. & Del Poeta, M. The cryptococcal enzyme inositol phosphosphingolipid-phospholipase C confers resistance to the antifungal effects of macrophages and promotes fungal dissemination to the central nervous system. Infect. Immun. 74, 5977–5988 (2006).
Kechichian, T. B., Shea, J. & Del Poeta, M. Depletion of alveolar macrophages decreases the dissemination of a glucosylceramide-deficient mutant of Cryptococcus neoformans in immunodeficient mice. Infect. Immun. 75, 4792–4798 (2007).
Charlier, C. et al. Capsule structure changes associated with Cryptococcus neoformans crossing of the blood-brain barrier. Am. J. Pathol. 166, 421–432 (2005).
Charlier, C. et al. Evidence of a role for monocytes in dissemination and brain invasion by Cryptococcus neoformans. Infect. Immun. 77, 120–127 (2009). Convincing evidence is presented to support the Trojan Horse mechanism for C. neoformans crossing the blood–brain barrier, and for a general role for monocytes in tissue seeding.
Shi, M. et al. Real-time imaging of trapping and urease-dependent transmigration of Cryptococcus neoformans in mouse brain. J. Clin. Invest. 120, 1683–1693 (2010). IVM demonstrates that C. neoformans cells are mechanically trapped in mouse brain capillaries and actively transmigrate to the brain parenchyma.
Wilson, R. A. & Talbot, N. J. Under pressure: investigating the biology of plant infection by Magnaporthe oryzae. Nature Rev. Microbiol. 7, 185–195 (2009).
Olszewski, M. A. et al. Urease expression by Cryptococcus neoformans promotes microvascular sequestration, thereby enhancing central nervous system invasion. Am. J. Pathol. 164, 1761–1771 (2004).
Lortholary, O. et al. Fungemia during murine cryptococcosis sheds some light on pathophysiology. Med. Mycol. 37, 169–174 (1999).
Chretien, F. et al. Pathogenesis of cerebral Cryptococcus neoformans infection after fungemia. J. Infect. Dis. 186, 522–530 (2002).
Alvarez, M. & Casadevall, A. Phagosome extrusion and host-cell survival after Cryptococcus neoformans phagocytosis by macrophages. Curr. Biol. 16, 2161–2165 (2006).
Levitz, S. M. et al. Cryptococcus neoformans resides in an acidic phagolysosome of human macrophages. Infect. Immun. 67, 885–890 (1999).
Tucker, S. C. & Casadevall, A. Replication of Cryptococcus neoformans in macrophages is accompanied by phagosomal permeabilization and accumulation of vesicles containing polysaccharide in the cytoplasm. Proc. Natl Acad. Sci. USA 99, 3165–3170 (2002).
Alvarez, M. & Casadevall, A. Cell-to-cell spread and massive vacuole formation after Cryptococcus neoformans infection of murine macrophages. BMC Immunol. 8, 16 (2007).
Ma, H., Croudace, J. E., Lammas, D. A. & May, R. C. Expulsion of live pathogenic yeast by macrophages. Curr. Biol. 16, 2156–2160 (2006).
Ma, H., Croudace, J. E., Lammas, D. A. & May, R. C. Direct cell-to-cell spread of a pathogenic yeast. BMC Immunol. 8, 15 (2007).
Johnston, S. A. & May, R. C. The human fungal pathogen Cryptococcus neoformans escapes macrophages by a phagosome emptying mechanism that is inhibited by Arp2/3 complex-mediated actin polymerisation. PLoS Pathog. 6, e1001041 (2010). This report finds evidence of repeated cycles of actin polymerization in phagosomes containing cryptococcal cells, producing cages that may temporarily inhibit expulsion of the fungal cells.
Yam, P. T. & Theriot, J. A. Repeated cycles of rapid actin assembly and disassembly on epithelial cell phagosomes. Mol. Biol. Cell 15, 5647–5658 (2004).
Ma, H. et al. The fatal fungal outbreak on Vancouver Island is characterized by enhanced intracellular parasitism driven by mitochondrial regulation. Proc. Natl Acad. Sci. USA 106, 12980–12985 (2009). This paper demonstrates that isolates from the British Columbia outbreak have an increased capacity to proliferate in macrophages, and show an altered mitochondrial morphology after phagocytosis. These results suggest that intracellular parasitic capability is an important component of the outbreak.
Cheng, P. Y., Sham, A. & Kronstad, J. W. Cryptococcus gattii isolates from the British Columbia cryptococcosis outbreak induce less protective inflammation in a murine model of infection than Cryptococcus neoformans. Infect. Immun. 77, 4284–4294 (2009). The first examination of immune response to the outbreak isolates demonstrates a reduced production of pro-inflammatory cytokines and a decrease in neutrophil infiltration in the lungs of mice infected with C. gattii , when compared with levels in mice infected with C. neoformans.
Cruickshank, J. G., Cavill, R. & Jelbert, M. Cryptococcus neoformans of unusual morphology. Appl. Microbiol. 25, 309–312 (1973).
Love, G. L., Boyd, G. D. & Greer, D. L. Large Cryptococcus neoformans isolated from brain abscess. J. Clin. Microbiol. 22, 1068–1070 (1985).
Sia, R. A., Lengeler, K. B. & Heitman, J. Diploid strains of the pathogenic basidiomycete Cryptococcus neoformans are thermally dimorphic. Fungal Genet. Biol. 29, 153–163 (2000).
Zaragoza, O., Fries, B. C. & Casadevall, A. Induction of capsule growth in Cryptococcus neoformans by mammalian serum and CO2 . Infect. Immun. 71, 6155–6164 (2003).
Zaragoza, O. et al. Fungal cell gigantism during mammalian infection. PLoS Pathog. 6, e1000945 (2010).
Nielsen, K. et al. Cryptococcus neoformans α strains preferentially disseminate to the central nervous system during coinfection. Infect. Immun. 73, 4922–4933 (2005).
Hsueh, Y. P. & Heitman, J. Orchestration of sexual reproduction and virulence by the fungal mating-type locus. Curr. Opin. Microbiol. 11, 517–524 (2008).
Okagaki, L. H. et al. Cryptococcal cell morphology affects host cell interactions and pathogenicity. PLoS Pathog. 6, e1000953 (2010). Along with reference 55, this study provides the first detailed characterization of giant cells and reveals their resistance to phagocytosis and their polyploid genome content.
Feldmesser, M., Kress, Y. & Casadevall A. Dynamic changes in the morphology of Cryptococcus neoformans during murine pulmonary infection. Microbiology 147, 2355–2365 (2001).
D'Souza, C. A. et al. Cyclic AMP-dependent protein kinase controls virulence of the fungal pathogen Cryptococcus neoformans. Mol. Cell. Biol. 21, 3179–3191 (2001).
Klein, B. S. & Tebbets, B. Dimorphism and virulence in fungi. Curr. Opin. Microbiol. 10, 314–319 (2007).
Desnos-Ollivier, M. et al. Mixed infections and in vivo evolution in the human fungal pathogen Cryptococcus neoformans. mBio 1, e00091–10 (2010). An intriguing survey of fresh isolates demonstrates that mixed infections with strains of different mating types, serotypes and genotypes are present in approximately 20% of patients. This study also reveals that transitions between haploid and diploid states can occur during infection.
Torres, E. M. et al. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317, 916–924 (2007).
Galitski, T., Saldanha, A. J., Styles, C. A., Lander, E. S. & Fink, G. R. Ploidy regulation of gene expression. Science 285, 251–254 (1999).
Selmecki, A., Forche, A. & Berman, J. Genomic plasticity of the human fungal pathogen Candida albicans. Eukaryot. Cell 9, 991–1008 (2010).
Fries, B. C., Chen, F., Currie, B. P. & Casadevall, A. Karyotype instability in Cryptococcus neoformans infection. J. Clin. Microbiol. 34, 1531–1534 (1996).
Loftus, B. J. et al. The genome of the basidiomycetous yeast and human pathogen Cryptococcus neoformans. Science 307, 1321–1324 (2005).
Kavanaugh, L. A., Fraser, J. A. & Dietrich, F. S. Recent evolution of the human pathogen Cryptococcus neoformans by intervarietal transfer of a 14-gene fragment. Mol. Biol. Evol. 23, 1879–1890 (2006).
D'Souza, C. A. et al. Genome variation in Cryptococcus gattii, an emerging pathogen of immunocompetent hosts. mBio (in the press). This paper reports the genome sequences of strains representing the VGI and VGII genotypes of C. gattii , as well as comparative genome hybridization experiments to examine variation in avirulent, fluconazole-resistant and outbreak isolates.
Hu, G. et al. Comparative hybridization reveals extensive genome variation in the AIDS-associated pathogen Cryptococcus neoformans. Genome Biol. 9, R41 (2008). The genome sequences of serotype A and serotype D strains are used in comparative studies to characterize genomic variability in strains of different molecular subtypes and in serotype AD hybrid strains. This analysis provides the first demonstration of disomy in clinical isolates of serotype A, the serotype that causes the majority of infections in patients with AIDS.
Sionov, E., Lee, H., Chang, Y. C. & Kwon-Chung, K. J. Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in specific multiple chromosomes. PLoS Pathog. 6, e1000848 (2010). This study reveals that extensive disomy is associated with drug resistance and that chromosomes encoding the target of fluconazole inhibition (Erg11) or a drug efflux pump (Afr1) have elevated copy number in resistant isolates.
Varma, A. & Kwon-Chung, K. J. Heteroresistance of Cryptococcus gattii to fluconazole. Antimicrob. Agents Chemother. 54, 2303–2311 (2010).
Guerrero, A., Jain, N., Wang, X. & Fries, B. C. Cryptococcus neoformans variants generated by phenotypic switching differ in virulence through effects on macrophage activation. Infect. Immun. 78, 1049–1057 (2010).
Lin, X. et al. Diploids in the Cryptococcus neoformans serotype A population homozygous for the α mating type originate via unisexual mating. PLoS Pathog. 5, e1000283 (2009).
Rancati, G. et al. Aneuploidy underlies rapid adaptive evolution of yeast cells deprived of a conserved cytokinesis motor. Cell 135, 879–893 (2008).
Duncan, A. W. et al. The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature 467, 707–710 (2010).
Liu, O. W. et al. Systematic genetic analysis of virulence in the human fungal pathogen Cryptococcus neoformans. Cell 135, 174–188 (2008).
CDC. Emergence of Cryptococcus gattii — Pacific Northwest, 2004–2010. MMWR 59, 865–868 (2010).
Fraser, J. A. et al. Same-sex mating and the origin of the Vancouver Island Cryptococcus gattii outbreak. Nature 437, 1360–1364 (2005).
Eisenman, H. C., Frases, S., Nicola, A. M., Rodrigues, M. L. & Casadevall, A. Vesicle-associated melanization in Cryptococcus neoformans. Microbiology 155, 3860–3867 (2009).
Rodrigues, M. L. et al. Vesicular polysaccharide export in Cryptococcus neoformans is a eukaryotic solution to the problem of fungal trans-cell wall transport. Eukaryot. Cell 6, 48–59 (2007).
Rodrigues, M. L. et al. Extracellular vesicles produced by Cryptococcus neoformans contain protein components associated with virulence. Eukaryot. Cell 7, 58–67 (2008).
Yoneda, A. & Doering, T. L. A eukaryotic capsular polysaccharide is synthesized intracellularly and secreted via exocytosis. Mol. Biol. Cell 17, 5131–5140 (2006).
Yoneda, A. & Doering, T. L. An unusual organelle in Cryptococcus neoformans links luminal pH and capsule biosynthesis. Fungal Genet. Biol. 46, 682–687 (2009).
Hu, G. et al. Transcriptional regulation by protein kinase A in Cryptococcus neoformans. PLoS Pathog. 3, e42 (2007).
Panepinto, J. et al. Sec6-dependent sorting of fungal extracellular exosomes and laccase of Cryptococcus neoformans. Mol. Microbiol. 71, 1165–1176 (2009).
Oliveira, D. L. et al. Extracellular vesicles from Cryptococcus neoformans modulate macrophage functions. Infect. Immun. 78, 1601–1609 (2010).
Levitz, S. M. & Specht, C. A. The molecular basis for the immunogenicity of Cryptococcus neoformans mannoproteins. FEMS Yeast Res. 6, 513–524 (2006).
Nosanchuk, J. D. & Casadevall, A. Impact of melanin on microbial virulence and clinical resistance to antimicrobial compounds. Antimicrob. Agents Chemother. 50, 3519–3528 (2006).
Panepinto, J. C. & Williamson, P. R. Intersection of fungal fitness and virulence in Cryptococcus neoformans. FEMS Yeast Res. 6, 489–498 (2006).
Zhu, X. & Williamson, P. R. Role of laccase in the biology and virulence of Cryptococcus neoformans. FEMS Yeast Res. 5, 1–10 (2004).
Perfect, J. R. Cryptococcus neoformans: the yeast that likes it hot. FEMS Yeast Res. 6, 463–468 (2006).
Brown, S. M., Campbell, L. T. & Lodge, J. K. Cryptococcus neoformans, a fungus under stress. Curr. Opin. Microbiol. 10, 320–325 (2007).
Siafakas, A. R. et al. Cell wall-linked cryptococcal phospholipase B1 is a source of secreted enzyme and a determinant of cell wall integrity. J. Biol. Chem. 282, 37508–37514 (2007).
Cox, G. M., Mukherjee, J., Cole, G. T., Casadevall, A. & Perfect, J. R. Urease as a virulence factor in experimental cryptococcosis. Infect. Immun. 68, 443–448 (2000).
de Jesús-BerrÃos, M. et al. Enzymes that counteract nitrosative stress promote fungal virulence. Curr. Biol. 13, 1963–1968 (2003).
Cox, G. M. et al. Superoxide dismutase influences the virulence of Cryptococcus neoformans by affecting growth within macrophages. Infect. Immun. 71, 173–180 (2003).
Gerik, K. J., Bhimireddy, S. R., Ryerse, J. S., Specht, C. A. & Lodge, J. K. PKC1 is essential for protection against both oxidative and nitrosative stresses, cell integrity, and normal manifestation of virulence factors in the pathogenic fungus Cryptococcus neoformans. Eukaryot. Cell 7, 1685–1698 (2008).
Hu, G. et al. PI3K signaling of autophagy is required for starvation tolerance and virulence of Cryptococcus neoformans. J. Clin. Invest. 118, 1186–1197 (2008).
Rhome, R. & Del Poeta, M. Lipid signaling in pathogenic fungi. Annu. Rev. Microbiol. 63, 119–131 (2009).
Bien, C. M. & Espenshade, P. J. Sterol regulatory element binding proteins in fungi: hypoxic transcription factors linked to pathogenesis. Eukaryot. Cell 9, 352–359 (2010).
Fan, W., Kraus, P. R., Boily, M. J. & Heitman, J. Cryptococcus neoformans gene expression during murine macrophage infection. Eukaryot. Cell 4, 1420–1433 (2005).
Hu, G., Cheng, P.-Y., Sham, A., Perfect, J. R. & Kronstad, J. W. Metabolic adaptation in Cryptococcus neoformans during early murine pulmonary infection. Mol. Microbiol. 69, 1456–1475 (2008).
Lin, X. & Heitman, J. The biology of the Cryptococcus neoformans species complex. Annu. Rev. Microbiol. 60, 69–105 (2006).
O'Meara, T. R. et al. Interaction of Cryptococcus neoformans Rim101 and protein kinase A regulates capsule. PLoS Pathog. 6, e1000776 (2010).
Jung, W. H., Sham, A., White, R. & Kronstad, J. W. Iron regulation of the major virulence factors in the AIDS-associated pathogen Cryptococcus neoformans. PLoS Biol. 4, e410 (2006).
Acknowledgements
We gratefully acknowledge support from the National Institute of Allergy and Infectious Diseases, US National Institutes of Health (RO1 AI053721) and the Canadian Institutes of Health Research. J.W.K. is a Burroughs Wellcome Fund Scholar in molecular pathogenic mycology.
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Glossary
- Meningoencephalitis
-
A combination of infection and inflammation of the meninges (membranes surrounding the central nervous system) and the brain.
- Capsule
-
A polysaccharide layer that surrounds cryptococcal cells and is composed of glucuronoxylomannan and galactoxylomannan.
- Melanin
-
A brown or black polymer that is deposited in the fungal cell wall and results in part from the catalytic activity of the enzyme laccase on substrates such as L-3,4-dihydroxyphenylalanine (L-DOPA), the dopamine precursor.
- Polyploid
-
Pertaining to a cell: containing more sets of chromosomes than a cell in the typical haploid (one set) or diploid (two sets) condition.
- Opsonization
-
The binding of an antibody or other protein to the surface of a pathogen cell to target that cell for phagocytosis.
- Dectin 1
-
(Also known as CLEC7A.) A receptor protein on the surface of immune effector cells that recognizes β-glucans on fungal cell walls to trigger an antifungal defence response.
- CR3
-
A member of the integrin adhesion receptor family that is expressed on leukocytes. CR3 is composed of a heterodimer of CD11b (also known as αM integrin or ITGAM) and CD18 (also known as ITGB2), and recognizes fungal mannose and β-glucans.
- Blood–brain barrier
-
A barrier that restricts the passage of solutes and microbes from the capillaries of the central nervous system into the brain. This barrier is created by capillary endothelial cells that are connected by tight junctions.
- Intravital microscopy
-
A technique for the direct microscopic observation of cellular interactions in the tissue of an anaesthetized animal. When coupled with spinning-disk confocal microscopy, the method allows images of optical sections of cells to be collected in narrow focal planes.
- Appressorium
-
A differentiated cell type that functions as an infection structure to mechanically penetrate the host surface; typically used by fungal pathogens to penetrate plant cell walls.
- Arp2/3 complex
-
A heptameric protein complex that is a major component of the actin cytoskeleton; the actin-related proteins Arp2 and Arp3 function in the nucleation of new actin filaments.
- WASP protein
-
A member of a family of proteins, named after Wiskott-Aldrich syndrome (which results from mutations in the WAS gene), that bind to and activate the Arp2/3 proteins for subsequent nucleation of actin filaments.
- Intracellular proliferation rate
-
A measure of the relative intracellular parasitism, calculated by dividing the maximum intracellular number of fungal cells in phagocytes by the number of cells at the start of an experiment.
- Serotype
-
A classification of cryptococcal isolates based on antibody recognition of the fungal polysaccharide capsule; Cryptococcus neoformans can be serotype A, D or AD, and Cryptococcus gattii can be serotype B or C.
- Endoreplication
-
DNA replication without subsequent mitosis, resulting in clear doubling events for the genome.
- Aneuploidy
-
The possession of an unusual complement of chromosomes, such as disomy arising from having two copies of a particular chromosome in a cell.
- Heteroresistance
-
A reversible, adaptive resistance to an antimicrobial drug such that a subpopulation of cells displays the ability to grow in the presence of the drug.
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Kronstad, J., Attarian, R., Cadieux, B. et al. Expanding fungal pathogenesis: Cryptococcus breaks out of the opportunistic box. Nat Rev Microbiol 9, 193–203 (2011). https://doi.org/10.1038/nrmicro2522
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DOI: https://doi.org/10.1038/nrmicro2522
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