Abstract
Cryptococcus neoformans is an encapsulated pathogenic yeast producing meningoencephalitis. Two primary strains in genetic studies, serotype A H99 and serotype D JEC21, possess dramatic differences in virulence. Since it has been shown that mitochondrial gene expression is prominent at the site of the infection and there are significant differences between mitochondrial gene structure and regulation between the serotype A and D strains, this study used AD hybrids to move serotype A and D mitochondria under different genomic influences. When the serotype D MATa strain is involved in the mating crosses, there is uniparental transmission of mitochondrial DNA, but with the serotype A MATa strain, mitochondrial DNA can be inherited from either parent and recombination in the mitochondrial genome may also occur. In virulence studies between serotype A and D strains, it was found that the primary genetic control of the virulence composite for growth in the central nervous system is encoded in the nuclear DNA and not through mitochondrial DNA.
Similar content being viewed by others
References
Alspaugh JA, Perfect JR, Heitman J (1997) Cryptococcus neoformans mating and virulence are regulated by the G-protein alpha subunit GPA1 and cAMP. Genes Dev 11:3206–3217
Alspaugh JA, Cavallo LM, Perfect JR, Heitman J (2000) RAS1 regulates filamentation, mating, and growth at high temperature of Cryptococcus neoformans. Mol Microbiol 36:352–365
Bastide PY de la, Horgen PA (2003) Mitochondrial inheritance and the detection of non-parental mitochondrial DNA haplotypes in crosses of Agaricus bisporus homokaryons. Fungal Genet Biol 38:333–342
Belcour L (1975) Cytoplasmic mutations isolated from protoplasts in Podospora anserina. Genet Res 25:155–161
Belcour L (2000) A circular mitochondrial plasmid incites hypovirulence in some strains of Cryphonectria parasitica. Curr Genet 37:242–256
Chang Y, Kwon-Chung KJ (1994) Complementation of a capsule-deficient mutation of Cryptococcus neoformans restores its virulence. Mol Cell Biol 14:4912–4919
Chang YC, Penoyer LA, Kwon-Chung KJ (1996) The second capsule gene of Cryptococcus neoformans, CAP64, is essential for virulence. Infect Immun 64:1977–1983
Chang YC, Wickes BL, Miller GF, Penoyer LA, Kwon-Chung KJ (2000) Cryptococcus neoformans STE12 alpha regulates virulence but is not essential for mating. J Exp Med 191:871–882
Chang YC, Penoyer LA, Kwon-Chung KJ (2001) The second STE12 homologue of Cryptococcus neoformans is MATa-specific and plays an important role in virulence. Proc Natl Acad Sci USA 98:3258–3263
Cox GM, Mukherjee J, Cole GT, Casadevall A, Perfect JR (2000) Urease as a virulence factor in experimental cryptococcosis. Infect Immun 68:443–448
Cox GM, McDade HC, Chen SC, et al (2001) Extracellular phospholipase activity is a virulence factor for Cryptococcus neoformans. Mol Microbiol 39:166–175
Cox GM, Harrison TS, Taborda CP, McDade HC, Heinrich G, Casadevall A, Perfect JR (2003) Superoxide dismutase influences the virulence of Cryptococcus neoformans by affecting growth within macrophages. Infect Immun 71:173–180
D’Souza CA, Alspaugh JA, Yue C, Harashima T, Cox GM, Perfect JR, Heitman J (2001) Cyclic-AMP-dependent protein kinase controls virulence of the fungal pathogen, C. neoformans. Mol Cell Biol 21:3179–3191
DiMauro S, Schon EA (2003) Mechanisms of disease: mitochondrial respiratory-chain diseases. N Engl J Med 348:2656–2668
Erickson T, Liu L, Gueylkian A, Zhu X, Gibbons J, Williamson PR (2001) Multiple virulence factors of Cryptococcus neoformans are dependent on VPH1. Mol Microbiol 42:1121–1131
Fujimura H, Sakuma Y (1993) Simplified isolation of chromosomal and plasmid DNA from yeasts. Biotechniques 14:538–540
Kwon-Chung KJ, Edman JC, Wickes BL (1992) Genetic association of mating types and virulence in Cryptococcus neoformans. Infect Immun 60:602–605
Lee SB, Taylor JW (1993) Uniparental inheritance and replacement of mitochondrial DNA in Neurospora tetrasperma. Genetics 134:1063–1075
Lengeler KB, Wang P, Cox GM, Perfect JR, Heitman J (2000) Identification of the MATa mating type locus of Cryptococcus reveals a serotype A MATa strain thought to have been extinct. Proc Nat Acad Sci USA 97:14455–14460
Lengeler KB, Cox GM, Heitman J (2001) Serotype AD strains of C. neoformans are diploid or aneuploid and are heterozygous at the mating-type locus. Infect Immun 69:115–122
Luberto C, Toffaletti DL, Wills EA, Tucker SC, Casadevall A, Perfect JR, Hannum YA, Del Poeta M (2001) Roles for inositol-phosphorylceramide synthase 1 (IPC1) in pathogenesis of C. neoformans. Genes Dev 15:201–212
Luberto C, Taraskiewicz D, Martinez-Marino B, Bolanos B, Chitano P, Toffaletti DL, Cox GM, Perfect JR, Hannun YA, Balish E, Del Poeta M (2003) IPC1 regulates the phagocytosis of Cryptococcus neoformans by macrophages through modulation of the antipagocytic protein (APP1) phagocytosis and pathogenicity: when host takes control. J Clin Invest 112:1080–1094
Mannella CA, Pittenger TH, Lambowitz AM (1979) Transmission of mitochondrial deoxyribonucleic acid in Neurospora crassa sexual crosses. J Bacteriol 137:1449–1451
Martinez LR, Garcia-Rivera J, Casadevall A (2001) Cryptococcus neoformans var. neoformans (serotype D) strains are more susceptible to heat than C. neoformans var. grubii (serotype A strains). J Clin Microbiol 39:3365–3367
Mason JR, Turner G (1975) Transmission and recombination of extranuclear genes during sexual crosses in Aspergillus nidulans. Mol Gen Genet 143:93–99
May G, Taylor JW (1988) Patterns of mating and mitochondrial DNA inheritance in the agaric Basidiomycete Coprinus cinereus. Genetics 118:213–220
Miletti KE, Leibowitz MJ (2000) Pentamidine inhibition of Group I intron splicing in Candida albicans correlates with growth inhibition. Antimicrob Agents Chemother 44:958–966
Neuveglise C, Brygoo Y, Riba G (1997) 28s rDNA group-I introns: a powerful tool for identifying strains of Beauveria brongniartii. Mol Ecol 6:373–381
Nielsen K, Cox GM, Wang P, Toffaletti DL, Perfect JR, Heitman J (2003) Establishment of the sexual cycle of Cryptococcus neoformans variety grubii and virulence of congenic a and alpha isolates. Infect Immun 71:4831–4841
Nyhus KJ, Ozaki LS, Jacobson ES (2002) Role of mitochondrial carrier protein Mrs 3/4 in iron acquisition and oxidative stress resistance of Cryptococcus neoformans. Med Mycol 40:581–591
Odom A, Muir S, Lim E, Toffaletti DL, Perfect JR, Heitman J (1997) Calcineurin is required for virulence of Cryptococcus neoformans. EMBO J 16:2576–2589
Olson A, Stenlid J (2001) Plant pathogens. Mitochondrial control of fungal hybrid virulence. Nature 411:438
Osiewacz HD, Kimpel E (1999) Mitochondrial–nuclear interactions and life span control in fungi. Exp Gerontol 34:901–909
Perfect JR (1989) Cryptococcosis. Infect Dis Clin North Am 3:77–102
Perfect JR, Casadevall A (2002) Cryptococcosis. Infect Dis Clin North Am 16:837–874
Perfect JR, Lang SDR, Durack DT (1980) Chronic cryptococcal meningitis: a new experimental model in rabbits. Am J Pathol 101:177–194
Pon L, Schatz G (1991) Biogenesis of yeast mitochondria. In: Broach JR, Pringle JR, Jones EW (eds) The molecular and cellular biology of the yeast Saccharomyces: genome dynamics, protein synthesis, and energetics, vol 1. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, pp 333–406
Salas SD, Bennett JE, Kwon-Chung KJ, Perfect JR, Williamson PR (1996) Effect of the laccase gene, CNLAC1, on virulence of Cryptococcus neoformans. J Exp Med 184:377–386
Specht CA, Novotny CP, Ullrich RC (1992) Mitochondrial DNA of Schizophyllum commune: restriction map, genetic map, and mode of inheritance. Curr Genet 22:129–134
Steen B, Zuderdyns S, Toffaletti DL, Marra M, Jones SJM, Perfect JR, Kronstad J (2003) Analysis of Cryptococcus neoformans gene expression during experimental cryptococcal meningitis. Eukaryot Cell 2:1336–1349
Toffaletti DL, Del Poeta M, Rude TH, Dietrich FS, Perfect JR (2003) Regulation of cytochrome C oxidase subunit 1 (COX1) expression in Cryptococcus neoformans by temperature and host environment. Microbiology 149:1041–1049
Wang P, Nichols CS, Lengeler KB, Cardenas ME, Cox GM, Perfect JR, Heitman J (2002) Mating type specific and nonspecific PAK kinases play shared and divergent role in cytokinesis, differentiation and virulence of Cryptococcus neoformans. Eukaryot Cell 1:257–272
Wilch G, Ward S, Castle A (1992) Transmission of mitochandrial DNA in Ustilago violacea. Curr Genet 22:135–140
Wills EA, Roberts IS, Del Poeta M, Rivera J, Casadevall A, Cox GM, Perfect JR (2001) Identification and characterization of the Cryptococcus neoformans phosphomannose isomerase-encoding gene, MAN1, and its impact on pathogenicity. Mol Microbiol 40:610–620
Xu J, Vilgalys R, Mitchell TG (2002) Multiple gene genealogies reveal recent dispersion and hybridization in the human fungus, Cryptococcus neoformans. Mol Ecol 9:1471–1481
Yan Z, Xu JP (2003) Mitochondria are inherited from the MATa parent in crosses of the basidiomycete fungus Cryptococcus neoformans. Genetics 163:1315–1325
Yost HJ, Lindquist S (1988) Translation of unspliced transcripts after heat shock. Science 242:1544–1548
Yue C, Cavallo L, Alspaugh JA, Cox GM, Perfect JR, Heitman J (1999) The STE12α homolog is required for haploid filamentation but dispensable for mating and virulence in Cryptococcus neoformans. Genetics 153:1601–1615
Zhang Y, Bell A, Perlman PS, Leibowitz MJ (2000) Pentamidine inhibits mitochondrial intron splicing and translation in Saccharomyces cervisiae. RNA 6:937–951
Acknowledgements
This work was supported by National Institute for Allergy and Infectious Disease (NIAID)-sponsored grants (AI 28388, AI 44975) and as a part of the Duke University Mycology Research Unit.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by M. Brunner
Rights and permissions
About this article
Cite this article
Toffaletti, D.L., Nielsen, K., Dietrich, F. et al. Cryptococcus neoformans mitochondrial genomes from serotype A and D strains do not influence virulence. Curr Genet 46, 193–204 (2004). https://doi.org/10.1007/s00294-004-0521-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00294-004-0521-9