Candida albicans (Ca) is a common opportunistic fungal pathogen that causes serious infections in immunocompromised patients. Drug resistance is increasing, and there is a need to identify new drug targets. Iron acquisition has been shown to be an important factor for virulence of bacteria, as well as for Ca. Knockout mutants lacking the CaFTR1 iron permease are avirulent in mouse models. We have found that Ca, in fact, uses three genetically and biochemically distinct iron uptake systems. A reductive system, requiring CaFTR1, is able to reduce and release ferric iron chelates, including transferrin chelates. A siderophore system mediates uptake of ferrisiderophore chelates of the ferrichrome type and requires the siderophore transporter CaSIT1. Finally, a heme iron utilization system requires heme oxygenase encoded by CaHMXl.
In Aim1 usage of the different systems will be tested under varied types of stress by measuring iron uptake from different substrates and by measuring expression of CaSIT1, CaFTR1 and CaHMX1. Deletion strains lacking in one of the iron uptake systems will be tested for growth properties, phenotypes and sensitivities.
In Aim 2, usage of the different uptake systems will be evaluated in model systems that include a model of oropharyngeal (epithelial) candidiasis, endothelial cell invasion, neutrophil interaction and intravenous infection of mice. Knockouts lacking individual uptake systems will be evaluated for their behavior in these model systems, with attention to deficits that may alter virulence. Finally in Aim 3, microarrays will be used to examine the effects of iron uptake from different iron sources (via different uptake systems) on expression of virulence genes. The hypothesis of this work is that different iron acquisition pathways are active in different host environments and may mediate virulent infections in those settings.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052384-04
Application #
7193433
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Duncan, Rory A
Project Start
2004-03-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
4
Fiscal Year
2007
Total Cost
$324,278
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104