The long-term goal of this research is to determine how environmental signals such as temperature regulate morphology and virulence in the fungal pathogen Histoplasma capsulatum. H. capsulatum grows in a filamentous form in the soil;once inhaled into a mammalian host, these cells switch their growth program to a parasitic yeast form that subverts the innate immune system to cause disease. A similar switch from soil to host form is observed for the evolutionarily related systemic dimorphic fungal pathogens, which include H. capsulatum as well as select agent pathogens such as Coccidioides species. For all of these pathogens, temperature is a key signal that regulates this morphogenetic switch, which is thought to be essential for H. capsulatum virulence. By elucidating how H. capsulatum cells sense and respond to host temperature, we will define critical molecular landmarks that promote changes in morphology as well as the expression of virulence traits. These studies will shed light on fundamental processes such as signal transduction and gene regulation, as well as uncover the role of temperature-dependent pathways in fungal pathogenesis. Over the last funding period, we identified the first transcriptional regulators required for growth in the yeast form in response to host temperature. These factors, named Ryp1, Ryp2, and Ryp3, are homologous to key developmental regulators in other fungi, and represent critical elements of the temperature-dependent regulatory circuit in H. capsulatum. Interestingly, the precise biochemical function of the orthologous regulators in other fungi is unclear, thus adding additional significance to our functional characterization in H. capsulatum. We have recently shown that the Ryp proteins associate with the upstream regions of both morphology and virulence genes, suggesting that they directly regulate essential components of the morphology and virulence programs. Furthermore, these data provide the first molecular evidence that the transcriptional regulation of morphology and virulence factors is coupled. In this proposal, our specific aims are to investigate and identify (1) the molecular mechanism of activation of the Ryp proteins by temperature;(2) the mechanisms by which the Ryp proteins regulate gene expression;and (3) the elements of the Ryp-dependent regulatory circuit that lie downstream of these factors and their effect on morphology and virulence. Taken together, the resultant data will greatly enhance our understanding of the molecular response pathway of H. capsulatum to host temperature. Additionally, we will gain valuable knowledge about individual morphology and virulence factors that are required for H. capsulatum pathogenesis in the host.

Public Health Relevance

Histoplasma capsulatum is a primary pathogen that infects approximately 500,000 individuals per year in the U.S. and is a significant source of morbidity and mortality in immunocompromised patients. Since very little is understood about how this fungus causes disease, the identification of fungal factors that influence pathogenesis and manipulate the host immune response will significantly advance the field and allow for the development of new therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI066224-08
Application #
8259478
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2005-05-15
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$344,149
Indirect Cost
$121,399
Name
University of California San Francisco
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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
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
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
Nguyen, Van Q; Sil, Anita (2008) Temperature-induced switch to the pathogenic yeast form of Histoplasma capsulatum requires Ryp1, a conserved transcriptional regulator. Proc Natl Acad Sci U S A 105:4880-5
Webster, Rachael Hanby; Sil, Anita (2008) Conserved factors Ryp2 and Ryp3 control cell morphology and infectious spore formation in the fungal pathogen Histoplasma capsulatum. Proc Natl Acad Sci U S A 105:14573-8

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