: The goal of this proposal is to determine the molecular mechanisms by which sexual development is controlled in the opportunistic human fungal pathogen Cryptococcus neoformans. Sexual development results in the production of spores that can be dispersed into the environment. C. neoformans is thought to infect humans from environmental sources via a respiratory route in which fungal spores are inhaled into the alveoli of the lungs. Once inhaled, C. neoformans can disseminate to the central nervous system and cause a fatal form of meningitis. Understanding the biology of sexual development and spore production in C. neoformans promises to provide information useful in the prevention and/or treatment of cryptococcal disease. This study is also of general interest because opportunistic fungi are emerging pathogens: understanding basic fungal biology sets the stage for the development of more effective methods of preventing and treating fungal disease in general. In C. neoformans sexual development is controlled by the Sex Inducer genes, SXI1a and SXI2a, but the mechanism by which they act is unknown. The experiments outlined in this proposal are designed to elucidate the mechanism by which SXI1a and SXI2a regulate gene expression to drive sexual differentiation. Using genetic, biochemical, bioinformatic, and cell biological approaches we will 1) map the regulatory circuit controlled by Sxi1a and Sxi2a by identifying and characterizing their downstream targets, 2) establish the properties of the Sxi1a and Sxi2a proteins required to control sexual development by evaluating the relationships between their structures and functions, and 3) investigate the cellular processes required for sexual development with a specific focus on dikaryotic filamentation. The diverse approaches presented here will elucidate the early stages of sexual development and lend new insights into how infectious particle production occurs in C. neoformans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI064287-01
Application #
6901445
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2005-04-01
Project End
2009-12-31
Budget Start
2005-04-01
Budget End
2005-12-31
Support Year
1
Fiscal Year
2005
Total Cost
$262,412
Indirect Cost
Name
University of Wisconsin Madison
Department
Biochemistry
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Mead, Matthew E; Stanton, Brynne C; Kruzel, Emilia K et al. (2015) Targets of the Sex Inducer homeodomain proteins are required for fungal development and virulence in Cryptococcus neoformans. Mol Microbiol 95:804-18
Botts, Michael R; Huang, Mingwei; Borchardt, Regen K et al. (2014) Developmental cell fate and virulence are linked to trehalose homeostasis in Cryptococcus neoformans. Eukaryot Cell 13:1158-68
Kruzel, Emilia K; Giles, Steven S; Hull, Christina M (2012) Analysis of Cryptococcus neoformans sexual development reveals rewiring of the pheromone-response network by a change in transcription factor identity. Genetics 191:435-49
Staudt, Mark W; Kruzel, Emilia K; Shimizu, Kiminori et al. (2010) Characterizing the role of the microtubule binding protein Bim1 in Cryptococcus neoformans. Fungal Genet Biol 47:310-7
Stanton, Brynne C; Giles, Steven S; Staudt, Mark W et al. (2010) Allelic exchange of pheromones and their receptors reprograms sexual identity in Cryptococcus neoformans. PLoS Genet 6:e1000860
Kruzel, Emilia K; Hull, Christina M (2010) Establishing an unusual cell type: how to make a dikaryon. Curr Opin Microbiol 13:706-11
Botts, Michael R; Hull, Christina M (2010) Dueling in the lung: how Cryptococcus spores race the host for survival. Curr Opin Microbiol 13:437-42
Dagenais, Taylor R T; Giles, Steve S; Aimanianda, Vishukumar et al. (2010) Aspergillus fumigatus LaeA-mediated phagocytosis is associated with a decreased hydrophobin layer. Infect Immun 78:823-9
Stanton, Brynne C; Giles, Steven S; Kruzel, Emilia K et al. (2009) Cognate Site Identifier analysis reveals novel binding properties of the Sex Inducer homeodomain proteins of Cryptococcus neoformans. Mol Microbiol 72:1334-47

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