: We seek to harness complete genome sequences to understand host-pathogen interactions that determine the ability of a fungal pathogen to cause disease in a mammalian host. The opportunistic pathogen Cryptococcus neoformans is a major cause of death in individuals with T lymphocyte defects, and is estimated to be the proximal cause of mortality in 5-10% of the 3 million deaths; caused by AIDS annually. C. neoformans is an excellent model organism for understanding fungal virulence because of its molecular manipulability, haploid genetics and faithful animal infection models. We have annotated the C. neoformans genome serotype A genome sequence, generated signature-tagged knockout mutants by gene targeting for -1200 genes (corresponding to about 20% of the genome), constructed and tested a whole-genome oligonucleotide DMA microarray, and initiated genetic screens for virulence factors in vitro and in a mouse in vivo infection model. We seek to continue to develop and utilize these tools to develop a comprehensive picture of pathogen genes necessary for virulence and to identify and to initiate more detailed studies of the subset involved in invasion of the central nervous system by C. neoformans. To achieve these goals we 1) complete construction of the C. neoformans knockout collection, 2) perform in vitro characterization of the knockout collection, 3) screen knockout collection for virulence mutants using a mouse model, and 4) identify and characterize mutants defective in invasion of the central nervous system. By systematically identifying molecules produced by C. neoformans important for virulence and by understanding how they function, we hope to lay the groundwork for the discovery of new therapies to treat fungal infections. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI065519-02
Application #
7078549
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2005-07-01
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$365,637
Indirect Cost
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143