The long-term goal of this research is to determine how temperature and other environmental signals regulate morphology and virulence in thermally dimorphic fungi, including 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. 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. We have been studying gene circuits that control cellular differentiation in response to temperature for the pas ten years, and have made a number of major contributions to the field. We have discovered four regulatory factors that are required for yeast-phase growth in response to temperature. We have dissected the regulon of each transcription factor and discovered that they share a number of key targets that are required for morphogenesis and pathogenesis. Over the next funding period, we will focus on understanding how these regulatory factors are activated by temperature. We have implicated a histidine kinase module, including two response regulator proteins, in direct control of this transcriptional network. We will exploit these findings and our expertise in H. capsulatum molecular genetics and biochemistry to uncover molecular mechanism that link temperature to changes in morphology and virulence. Additionally, we will mine our rich and unexplored datasets of target genes to identify novel virulence factors that are induced by temperature. This work will uncover fundamental molecular properties of the yeast cell that are regulated by temperature. Ultimately our work will uncover the major molecular transitions that allow this fungus to cause disease within mammalian hosts.

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. The identification and characterization of regulatory pathways that influence cell shape and pathogenesis will significantly advance our understanding of how this organism responds to host signals such as temperature to cause disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI066224-12
Application #
9053432
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2005-05-15
Project End
2020-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
12
Fiscal Year
2016
Total Cost
Indirect Cost
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
94118
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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