Irreversible Block of the Mycelial-to-Yeast Phase Transition of
            <i>Histoplasma capsulatum</i>

Medoff, Gerald; Sacco, Margherita; Maresca, Bruno; Schlessinger, David; Painter, Audrey A.; Kobayashi, George S.; Carratù, Luisella

doi:10.1126/science.3001938

Cited by 108 publications

(59 citation statements)

References 20 publications

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“…Infection with temperature-sensitive mutants which may not have the sulfhydryl shunt pathways might provide effective protection. Another possibility is the use of mycelia treated with the sulfhydryl inhibitor parachloromercuriphenylsulfonic acid, which blocks the mycelial-to yeast-phase transition of H. capsulatum (6).…”

Section: Discussionmentioning

confidence: 99%

Mycelial- to yeast-phase transitions of the dimorphic fungi Blastomyces dermatitidis and Paracoccidioides brasiliensis

Medoff¹,

Painter²,

Kobayashi³

1987

J Bacteriol

105

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The physiological changes that occur during the mycelial-to yeast-phase transitions induced by a temperature shift from 25 to 37°C of cultures of Blastomyces dermatitidis and Paracoccidioides brasiliensis can be divided into three stages. The triggering event is a heat-related insult induced by the temperature shift which results in partial uncoupling of oxidative phosphorylation and declines in cellular ATP levels, respiration rates, and concentrations of electron transport components (stage 1). The cells then enter a stage in which spontaneous respiration ceases (stage 2), and finally, there is a shift into a recovery phase during Which transformation to yeast morphology occurs (stage 3). Cysteine is required during stage 2 for the operation of shunt pathways which permit electron transport to bypass blocked portions of the cytochrome system. The mycelial-to yeast-phase transitions of these two fungi are very similar to that of Histoplasma capsulatum. Therefore, these three dimorphic fungal pathogens have evolved parallel mechanisms to adjust to the temperature shifts which induce these mycelial-to yeast-phase transitions.Blastomyces dermatitidis, Paracoccidioides brasiliensis, and Histoplasma capsulatum are dimorphic pathogenic fungi. Although there are some differences in geographic distribution and clinical presentation of disease caused by these fungi, they all can cause systemic infections in humans. Other similarities include the existence as mycelia in nature and yeast in infected tissue, growth as mycelia in cultures incubated at 25°C and as yeast at 370C, and induction of reversible phase transitions by switching between 25 and 37°C (7).In previous studies (5, 5a, 8) we characterized the mycelial-to yeast-phase transition of H. capsulatum induced by the temperature shift from 25 to 37°C and also by shifts to temperatures as high as 43°C. We found that the physiological changes that occur in this fungus when the temperature is raised can be divided into three distinct stages. Stage 1, which immediately follows the temperature shift, is characterized by partial or complete uncoupling of oxidative phosphorylation, an immediate decline in ATP levels, and a progressive decrease in respiration rates over 24 h. After 24 to 40 h, the cells enter stage 2, a dormant period of 4 to 6 days that is characterized by absent or low rates of respiration, decreased concentrations of mitochondrial electron transport components, and inhibition of RNA and protein synthesis. Stage 3 is characterized by increasing concentrations of cytochrome components, resumption of normal respiration, and completion of the transition to yeast morphology.The severity of the changes during the transition depends on the thermal tolerance of the strain of H. capsulatum and the level of the temperature of incubation (7). When the temperature elevation is high enough, spontaneous respiration ceases in stage 2, and cysteine or other sulfhydrylcontaining compounds are required for the operation of shunt pathways which permit electron transport t...

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Section: Discussionmentioning

confidence: 99%

Mycelial- to yeast-phase transitions of the dimorphic fungi Blastomyces dermatitidis and Paracoccidioides brasiliensis

Medoff¹,

Painter²,

Kobayashi³

1987

J Bacteriol

105

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“…The identification of dimorphism genes from pathogenic fungi will be interesting because dimorphism appears to be involved in the virulence of several fungal pathogens of animals and plants (7,67). For instance, the unicellular growth mode of the human pathogen Histoplasma capsulatum is associated with disease, while the filamentous phase appears to be avirulent (49,50). A drug that could lock H. capsulatum in its avirulent filamentous state might be an effective antifungal agent.…”

Section: Agcgtcgcacgtccaaataaccttaaatcaatagcagcagcgtcaccaacagtgacagcamentioning

confidence: 99%

Induction of pseudohyphal growth by overexpression of PHD1, a Saccharomyces cerevisiae gene related to transcriptional regulators of fungal development.

1994

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When starved for nitrogen, AMTa/AMTo cells of the budding yeast Saccharomyces cerevisiae undergo a dimorphic transition to pseudohyphal growth. A visual genetic screen, called PHD (pseudohyphal determinant), for S. cerevisiae pseudohyphal growth mutants was developed. The PHD screen was used to identify seven S. cerevisiae genes that when overexpressed in AMTa/MAMTot cells growing on nitrogen starvation medium cause precocious and unusually vigorous pseudohyphal growth. PHDI, a gene whose overexpression induced invasive pseudohyphal growth on a nutritionally rich medium, was characterized. PHDI maps to chromosome XI and is predicted to encode a 366-amino-acid protein. PHD1 has a SWI4-and MBP1-like DNA binding motif that is 73% identical over 100 amino acids to a region ofAspergillus nidulans StuA. StuA regulates two pseudohyphal growth-like cell divisions during conidiophore morphogenesis. Epitope-tagged PHD1 was localized to the nucleus by indirect immunofluorescence. These facts suggest that PHD1 may function as a transcriptional regulatory protein. Overexpression ofPHDI in wild-type haploid strains does not induce pseudohyphal growth. Interestingly, PHDI overexpression enhances pseudohyphal growth in a haploid strain that has the diploid polar budding pattern because of a mutation in the BUD4 gene. In addition, wild-type diploid strains lacking PHDI undergo pseudohyphal growth when starved for nitrogen. The possible functions of PHDI in pseudohyphal growth and the uses of the PHD screen to identify morphogenetic regulatory genes from heterologous organisms are discussed.

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“…This dimorphism is essential for virulence; chemically treated mycelial cultures that are unable to make the transition to yeasts are avirulent (26). Dimorphism is also the best-studied system of H. capsulatum gene regulation, and both moldphase-specific and yeast-phase-specific genes have been identified (7, 13, 15-18, 28, 32, 33).…”

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confidence: 99%

Surface Localization of the Yps3p Protein of Histoplasma capsulatum

Bohse

Woods

2005

Eukaryot Cell

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The YPS3 gene of Histoplasma capsulatum encodes a protein that is both resident in the cell wall and also released into the culture medium. This protein is produced only during the pathogenic yeast phase of infection and is also expressed differently in H. capsulatum strains that differ in virulence. We investigated the cellular localization of Yps3p. We demonstrated that the cell wall fraction of Yps3p was surface localized in restriction fragment length polymorphism class 2 strains. We also established that Yps3p released into the G217B culture supernatant binds to the surface of strains that do not naturally express the protein. This binding was saturable and occurred within 5 min of exposure and occurred similarly with live and heat-killed H. capsulatum. Flow cytometric analysis of H. capsulatum after enzymatic treatments was consistent with Yps3p binding to chitin, a carbohydrate polymer that is a component of fungal cell walls. Polysaccharide binding assays demonstrated that chitin but not cellulose binds to and extracts Yps3p from culture supernatants.

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Irreversible Block of the Mycelial-to-Yeast Phase Transition of Histoplasma capsulatum

Cited by 108 publications

References 20 publications

Mycelial- to yeast-phase transitions of the dimorphic fungi Blastomyces dermatitidis and Paracoccidioides brasiliensis

Mycelial- to yeast-phase transitions of the dimorphic fungi Blastomyces dermatitidis and Paracoccidioides brasiliensis

Induction of pseudohyphal growth by overexpression of PHD1, a Saccharomyces cerevisiae gene related to transcriptional regulators of fungal development.

Surface Localization of the Yps3p Protein of Histoplasma capsulatum

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