The long-term goal of our research is to understand how the fungal pathogen Histoplasma capsulatum causes disease. H. capsulatum is a highly virulent pathogen that causes significant morbidity in both immunocompromised and immunocompetent individuals, with approximately 500,000 Histoplasma infections estimated to occur every year in the U.S. H. capsulatum is a pathogen of macrophages, which phagocytose microbes and digest them via an arsenal of microbicidal mechanisms. In contrast to most microbes, H. capsulatum replicates to high levels in the macrophage phagosome. Colonization of the macrophage is followed by host-cell death and release of live yeast cells, but the mechanism that triggers host-cell death is unknown. We have determined that the previously identified Histoplasma factor Cbp1 is dispensable for high intracellular fungal burden, but required for host-cell lysis. Additionally, our preliminary studies uncovered that Cbp1 is required to induce transcription of a specific and limited set of macrophage genes during infection, which we have named the Histoplasma response cluster (HRC). We hypothesize that Cbp1 interacts with unknown host factors, resulting in the induction of this unique transcriptional signature as well as host-cell death. Here we will (1) investigate whether Cbp1 triggers host-cell death by established or novel pathways, (2) determine which molecular characteristics of Cpb1 are important for host cell death, (3) establish if Cbp1 is required for pathogenesis of human macrophages, and (4) assess the role of Cbp1 in host-cell death and inflammation in the mouse model of histoplasmosis. These studies will generate new paradigms of virulence strategies used by human fungal pathogens during infection. Additionally, identifying host pathways that are potential targets of Cbp1, as well as understanding how Cbp1-modulated host-cell death contributes to disease progression, will significantly enrich our understanding of how eukaryotic pathogens have evolved to manipulate their 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 in immunocompromised patients. The characterization of a fungal virulence factor from H. capsulatum will significantly advance our understanding of how this organism causes disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI093640-01A1
Application #
8245483
Study Section
Special Emphasis Panel (ZRG1-IDM-B (02))
Program Officer
Duncan, Rory A
Project Start
2012-04-15
Project End
2016-03-31
Budget Start
2012-04-15
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$378,493
Indirect Cost
$128,493
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
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