The incidence of bloodstream infections caused by Candida species has increased dramatically; these organisms now account for 10% of all bloodstream isolates. The mortality associated with candidemia approaches 40%, even with therapy. Because of this unacceptably high mortality, new strategies to treat and prevent this infection are necessary. Our goal is to identify new Candida albicans virulence genes and to determine the mechanisms by which they contribute to pathogenicity. This information holds promise to identify new targets for antifungal strategies. Our hypothesis is that the ability of C. albicans to invade and damage host cells is critical for the organism to establish and maintain a deep-seated infection. Support for this hypothesis comes from our finding that many C. albicans mutants with decreased virulence in the mouse model of hematogenously disseminated infection also have reduced ability to invade and damage endothelial cells in vitro. Furthermore, we have screened a collection of random C. albicans homozygous insertion mutants to identify strains with impaired capacity to damage endothelial cells in vitro. We discovered that zed1/zed1 and cka2/cka2 insertion mutants caused much less endothelial cell damage than did the isogenic control strain. Also, the zed1/zed1 insertion mutant had significantly attenuated virulence in mice (the virulence of the cka2/cka2 strain has not yet been tested). These results strongly suggest that C. albicans genes required for in vitro endothelial cell damage are also required for virulence. Our objective is to use in vitro studies of the interactions between C. albicans and endothelial cells to define mechanisms of host-pathogen interaction. In this project, we will 1) identify the endothelial cell receptors that C. albicans uses to invade this host cell; 2) determine the mechanisms by which C. albicans Zed1p, Cka2p, and other newly identified gene products contribute to virulence; 3) use defined C. albicans mutants to elucidate functional relationships among C. albicans virulence regulators, endothelial cell receptors, and endothelial cell damage; and 4) use a random insertional mutagenesis approach to identify new C. albicans genes that promote endothelial cell damage in vitro and virulence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054928-02
Application #
6845968
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Duncan, Rory A
Project Start
2004-01-20
Project End
2008-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
2
Fiscal Year
2005
Total Cost
$291,425
Indirect Cost
Name
La Biomed Research Institute/ Harbor UCLA Medical Center
Department
Type
DUNS #
069926962
City
Torrance
State
CA
Country
United States
Zip Code
90502
Xu, Wenjie; Solis, Norma V; Filler, Scott G et al. (2016) Gene Expression Profiling of Infecting Microbes Using a Digital Bar-coding Platform. J Vis Exp :e53460
Gebremariam, Teclegiorgis; Lin, Lin; Liu, Mingfu et al. (2016) Bicarbonate correction of ketoacidosis alters host-pathogen interactions and alleviates mucormycosis. J Clin Invest 126:2280-94
Chibucos, Marcus C; Soliman, Sameh; Gebremariam, Teclegiorgis et al. (2016) An integrated genomic and transcriptomic survey of mucormycosis-causing fungi. Nat Commun 7:12218
Xu, Wenjie; Solis, Norma V; Filler, Scott G et al. (2016) Pathogen Gene Expression Profiling During Infection Using a Nanostring nCounter Platform. Methods Mol Biol 1361:57-65
Liu, Yaoping; Shetty, Amol C; Schwartz, Jennifer A et al. (2015) New signaling pathways govern the host response to C. albicans infection in various niches. Genome Res 25:679-89
Shankar, Jyoti; Solis, Norma V; Mounaud, Stephanie et al. (2015) Using Bayesian modelling to investigate factors governing antibiotic-induced Candida albicans colonization of the GI tract. Sci Rep 5:8131
Shankar, Jyoti; Szpakowski, Sebastian; Solis, Norma V et al. (2015) A systematic evaluation of high-dimensional, ensemble-based regression for exploring large model spaces in microbiome analyses. BMC Bioinformatics 16:31
Xu, Wenjie; Solis, Norma V; Ehrlich, Rachel L et al. (2015) Activation and alliance of regulatory pathways in C. albicans during mammalian infection. PLoS Biol 13:e1002076
Liu, Yaoping; Solis, Norma V; Heilmann, Clemens J et al. (2014) Role of retrograde trafficking in stress response, host cell interactions, and virulence of Candida albicans. Eukaryot Cell 13:279-87
Filler, Scott G (2014) In vitro models of hematogenously disseminated candidiasis. Virulence 5:240-2

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