Regulation of Cryptococcal Capsular Polysaccharide by Iron

Vartivarian, Shahe; Anaissie, Elias; Cowart, Richard E.; Sprigg, Helen A.; Tingler, Mary Jean; Jacobson, Eric S.

doi:10.1093/infdis/167.1.186

Cited by 196 publications

(187 citation statements)

References 14 publications

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“…neoformans is distinguished from many pathogenic yeast by its polysaccharide capsule, which inhibits phagocytosis by host cells and is required for virulence (3). Formation of the capsule is induced during infection or in response to low-iron or elevated-CO 2 conditions in vitro (16,55). To assess capsule production, the wild-type strain H99 and the gpa1 and gpb1 mutant strains were grown in liquid iron-limiting medium.…”

Section: Resultsmentioning

confidence: 99%

The G-Protein β Subunit GPB1 Is Required for Mating and Haploid Fruiting in Cryptococcus neoformans

Wang¹,

Perfect²,

Heitman

2000

Molecular and Cellular Biology

161

150

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Cryptococcus neoformans is an opportunistic fungal pathogen with a defined sexual cycle. The gene encoding a heterotrimeric G-protein ␤ subunit, GPB1, was cloned and disrupted. gpb1 mutant strains are sterile, indicating a role for this gene in mating. GPB1 plays an active role in mediating responses to pheromones in early mating steps (conjugation tube formation and cell fusion) and signals via a mitogen-activated protein (MAP) kinase cascade in both MAT␣ and MATa cells. The functions of GPB1 are distinct from those of the G␣ protein GPA1, which functions in a nutrient-sensing cyclic AMP (cAMP) pathway required for mating, virulence factor induction, and virulence. gpb1 mutant strains are also defective in monokaryotic fruiting in response to nitrogen starvation. We show that MATa cells stimulate monokaryotic fruiting of MAT␣ cells, possibly in response to mating pheromone, which may serve to disperse cells and spores to locate mating partners. In summary, the G␤ subunit GPB1 and the G␣ subunit GPA1 function in distinct signaling pathways: one (GPB1) senses pheromones and regulates mating and haploid fruiting via a MAP kinase cascade, and the other (GPA1) senses nutrients and regulates mating, virulence factors, and pathogenicity via a cAMP cascade.Cryptococcus neoformans is an opportunistic fungal pathogen that infects the central nervous system to cause meningoencephalitis in individuals with compromised immune function (26,39). Virulence is associated with mating type (28), production of melanin (29,30,48,56) and a polysaccharide capsule (4,16,30), and growth at 37°C (30, 45).The life cycle of this organism has been defined (25). Mating occurs between MATa and MAT␣ cells and involves cell fusion, filamentation, nuclear migration and fusion, meiosis, and sporulation. Mating type is linked to physiology and virulence. MAT␣ strains are more prevalent in the environment, and most clinical isolates are MAT␣ (27); MAT␣ strains are more virulent in mice than are congenic MATa strains (28). In response to nitrogen starvation, MAT␣ cells differentiate to form filaments, basidia, and spores (haploid fruiting) (62). Thus, genes linked to the MAT␣ locus regulate the physiology and virulence of C. neoformans. A homolog of the Saccharomyces cerevisiae and Candida albicans STE12 transcription factor is encoded by the C. neoformans MAT␣ locus (61), and ste12 mutant strains have defects in haploid fruiting (67). Recent studies of a GTP-binding protein, GPA1, underscore the importance of signaling cascades in C. neoformans virulence (2, 54).Heterotrimeric guanine nucleotide binding proteins interact with G-protein-coupled receptors to sense external signals and regulate cell growth and development (14). G-protein-mediated signals include responses to hormones and neurotransmitters, vision and olfaction, and pheromone-induced mating in S. cerevisiae and Schizosaccharomyces pombe. Heterotrimeric G proteins are comprised of alpha (␣), beta (␤), and gamma (␥) subunits. In response to binding of ligand to receptors, the G␣␤␥ compl...

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Section: Resultsmentioning

confidence: 99%

The G-Protein β Subunit GPB1 Is Required for Mating and Haploid Fruiting in Cryptococcus neoformans

Wang¹,

Perfect²,

Heitman

2000

Molecular and Cellular Biology

161

150

View full text Add to dashboard Cite

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“…Standard yeast media were used for most experiments (Sherman, 1991). Niger seed agar and V8 mating medium (Kwon-Chung & Bennett, 1992), and noiron medium (low-iron mediumj56 µM EDDHA) (Vartivarian et al, 1993) were prepared as described previously (Alspaugh et al, 2000).…”

Section: Methodsmentioning

confidence: 99%

Ras1 and Ras2 contribute shared and unique roles in physiology and virulence of Cryptococcus neoformans The GenBank accession number for the RAS2 sequence of C. neoformans H99 is AF294349.

et al. 2002

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The Ras1 signal transduction pathway controls the ability of the pathogenic fungus Cryptococcus neoformans to grow at high temperatures and to mate. A second RAS gene was identified in this organism. RAS2 is expressed at a very low level compared to RAS1, and a ras2 mutation caused no alterations in vegetative growth rate, differentiation or virulence factor expression. The ras2 mutant strain was equally virulent to the wild-type strain in the murine inhalational model of cryptococcosis. Although a ras1 ras2 double mutant strain is viable, mutation of both RAS genes results in a decreased growth rate at all temperatures compared to strains with either single mutation. Overexpression of the RAS2 gene completely suppressed the ras1 mutant mating defect and partially suppressed its high temperature growth defect. After prolonged incubation at a restrictive temperature, the ras1 mutant demonstrated actin polarity defects that were also partially suppressed by RAS2 overexpression. These studies indicate that the C. neoformans Ras1 and Ras2 proteins share overlapping functions, but also play distinct signalling roles. Our findings also suggest a mechanism by which Ras1 controls growth of this pathogenic fungus at 37 mC, supporting a conserved role for Ras homologues in microbial cellular differentiation, morphogenesis and virulence.

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“…The polysaccharide capsule is induced in vivo in the infected host by iron limitation and carbon dioxide and surrounds and protects fungal cells from phagocytosis and enhances intracellular survival in macrophages (24,28,74). In addition, capsular antigens are shed into the circulation and have potent immunosuppressive activity (18,19,32,75,76).…”

mentioning

confidence: 99%

Cyclic AMP-Dependent Protein Kinase Controls Virulence of the Fungal Pathogen Cryptococcus neoformans

D’Souza¹,

Alspaugh²,

Yue³

et al. 2001

Molecular and Cellular Biology

315

392

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Cryptococcus neoformans is an opportunistic fungal pathogen that infects the human central nervous system. This pathogen elaborates two specialized virulence factors: the antioxidant melanin and an antiphagocytic immunosuppressive polysaccharide capsule. A signaling cascade controlling mating and virulence was identified. The PKA1 gene encoding the major cyclic AMP (cAMP)-dependent protein kinase catalytic subunit was identified and disrupted. pka1 mutant strains were sterile, failed to produce melanin or capsule, and were avirulent. The PKR1 gene encoding the protein kinase A (PKA) regulatory subunit was also identified and disrupted. pkr1 mutant strains overproduced capsule and were hypervirulent in animal models of cryptococcosis. pkr1 pka1 double mutant strains exhibited phenotypes similar to that of pka1 mutants, providing epistasis evidence that the Pka1 catalytic subunit functions downstream of the Pkr1 regulatory subunit. The PKA pathway was also shown to function downstream of the G␣ protein Gpa1 and to regulate cAMP production by feedback inhibition. These findings define a G␣ protein-cAMP-PKA signaling pathway regulating differentiation and virulence of a human fungal pathogen.

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Regulation of Cryptococcal Capsular Polysaccharide by Iron

Cited by 196 publications

References 14 publications

The G-Protein β Subunit GPB1 Is Required for Mating and Haploid Fruiting in Cryptococcus neoformans

The G-Protein β Subunit GPB1 Is Required for Mating and Haploid Fruiting in Cryptococcus neoformans

Ras1 and Ras2 contribute shared and unique roles in physiology and virulence of Cryptococcus neoformans The GenBank accession number for the RAS2 sequence of C. neoformans H99 is AF294349.

Cyclic AMP-Dependent Protein Kinase Controls Virulence of the Fungal Pathogen Cryptococcus neoformans

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