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Member Information
Andrew Dancis, MD
Associate Professor, Department of Hematology/Oncology
Office Phone: 215 573-6275
Office Fax: 215 573-7049
Email: adancis@mail.med.upenn.edu
Website(s): http://www.uphs.upenn.edu/hematol/faculty/dancis.htm
Education:
Keywords: Neutropenia, Iron, Heme, Fungal Disease, Candida Albicans
Research and/or Clinical Interests:
Determining the role of specific iron acquisition systems in virulence of Candida albicans infections
Summary:
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. 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 CaHMX1.
We are evaluating usage of the different systems 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 are being tested for growth properties, phenotypes and sensitivities. Usage of the different uptake systems are being evaluated in model systems that include a model of oropharyngeal (epithelial) candidiasis, enothelial cell invasion, neutrophil interaction and intravenous infectionof mice. Knockouts lacking individual uptake systems are being tested for their behaviour in these model systems, with attention to deficits that may alter virulence. Finally microarrays are being 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 by Candida albicans in those settings.
Representative Publications:
Lesuisse, E., Blaiseau, P-L., Dancis, A., Camadro, J-M. (2001) Siderophore uptake and utilization by the yeast Saccharomyces cerevisiae. Microbiol. 147: 289-298.
Kim, R., Saxena, S., Gordon, D. M., Pain, D., Dancis, A. (2001) J-domain protein, Jac1p, of yeast mitochondria required for iron homeostasis and activity of Fe-S cluster proteins. J. Biol. Chem. 276: 17524-17532.
Lesuisse, E., Knight, S. A. B., Camadro, J-M., Dancis, A. (2001) Siderophore uptake by Candida albicans : relationship to the dimorphic transition and comparison with Saccharomyces cerevisiae . Yeast 19: 329-340.
Knight, S. A. B., Lesuisse, E., Stearman, R., Klausner, R. D., Dancis, A. (2002) Reductive iron uptake by Candida albicans : role of copper, iron, and the TUP1 regulator. Microbiol. 148: 29-40.
Santos , R., Buisson, N., Knight, S., Dancis, A., Camadro, J-M., Lesuisse, E. (2003) Haemin uptake and use as an iron source by Candida albicans: role of CaHMX1 encoded haem oxygenase. Microbiol. 149: 579-588.
Lesuisse, E., Santos , R., Matzanke, B. F., Camadro, J-M., Knight, S. A. B., Dancis, A. (2003) Iron use for heme synthesis is under control of the yeast frataxin homologue (Yfh1). Hum. Mol. Genet. 12: 879-889.
