: Fungal infections are a growing medical threat, particularly for immunocompromised individuals. A molecular understanding of how fungal pathogens sense and respond to their environment will strengthen our ability to identify the Achilles'heel of these organisms for therapeutic purposes. The long-term goal of this research project is to determine how environmental signals regulate morphology and virulence in the fungal pathogen Histoplasma capsulatum. H. capsulatum grows in a filamentous mold (mycelial) form in the soil and a budding yeast form in the host. The transition from the mycelial form to the yeast form is thought to be essential for virulence. Although temperature is known to be a key signal that triggers the conversion between the two forms of H. capsulatum, little is known about the molecular mechanism of how temperature regulates morphology. We hypothesize that H. capsulatum uses conserved signal transduction pathways converging on master transcription factors to regulate morphology in response to temperature. The objective of this proposal is to use genetics and functional genomics to identify key molecules that are required for this process.
Our specific aims are (1) to perform a genetic screen using a high throughput colony morphology assay to identify genes required for normal morphology in response to temperature;(2) to use gene expression profiling as a sensitive assay to characterize the function of regulators of morphology;and (3) to further characterize the function of putative regulators of morphology using molecular genetic experiments such as gene inactivation, ectopic expression, and subcellular localization. These studies will generate an understanding of the regulatory circuits used by H. capsulatum to shift its growth program in response to environmental signals. Moreover, the proposed research will elucidate the mechanism of how H. capsulatum regulates virulence properties in response to temperature.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Pathogenic Eukaryotes Study Section (PTHE)
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Duncan, Rory A
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Gilmore, Sarah A; Voorhies, Mark; Gebhart, Dana et al. (2015) Genome-Wide Reprogramming of Transcript Architecture by Temperature Specifies the Developmental States of the Human Pathogen Histoplasma. PLoS Genet 11:e1005395
Isaac, Dervla T; Berkes, Charlotte A; English, Bevin C et al. (2015) Macrophage cell death and transcriptional response are actively triggered by the fungal virulence factor Cbp1 during H. capsulatum infection. Mol Microbiol 98:910-929
Beyhan, Sinem; Gutierrez, Matias; Voorhies, Mark et al. (2013) A temperature-responsive network links cell shape and virulence traits in a primary fungal pathogen. PLoS Biol 11:e1001614
Isaac, Dervla T; Coady, Alison; Van Prooyen, Nancy et al. (2013) The 3-hydroxy-methylglutaryl coenzyme A lyase HCL1 is required for macrophage colonization by human fungal pathogen Histoplasma capsulatum. Infect Immun 81:411-20
Inglis, Diane O; Voorhies, Mark; Hocking Murray, Davina R et al. (2013) Comparative transcriptomics of infectious spores from the fungal pathogen Histoplasma capsulatum reveals a core set of transcripts that specify infectious and pathogenic states. Eukaryot Cell 12:828-52
Gilmore, Sarah A; Naseem, Shamoon; Konopka, James B et al. (2013) N-acetylglucosamine (GlcNAc) triggers a rapid, temperature-responsive morphogenetic program in thermally dimorphic fungi. PLoS Genet 9:e1003799
Hwang, Lena H; Seth, Erica; Gilmore, Sarah A et al. (2012) SRE1 regulates iron-dependent and -independent pathways in the fungal pathogen Histoplasma capsulatum. Eukaryot Cell 11:16-25
Voorhies, Mark; Foo, Catherine K; Sil, Anita (2011) Experimental annotation of the human pathogen Histoplasma capsulatum transcribed regions using high-resolution tiling arrays. BMC Microbiol 11:216
Inglis, Diane O; Berkes, Charlotte A; Hocking Murray, Davina R et al. (2010) Conidia but not yeast cells of the fungal pathogen Histoplasma capsulatum trigger a type I interferon innate immune response in murine macrophages. Infect Immun 78:3871-82
Hwang, Lena H; Mayfield, Jacob A; Rine, Jasper et al. (2008) Histoplasma requires SID1, a member of an iron-regulated siderophore gene cluster, for host colonization. PLoS Pathog 4:e1000044

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