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Published May 2015 | Published + Supplemental Material
Journal Article Open

Fob1 and Fob2 Proteins Are Virulence Determinants of Rhizopus oryzae via Facilitating Iron Uptake from Ferrioxamine


Dialysis patients with chronic renal failure receiving deferoxamine for treating iron overload are uniquely predisposed for mucormycosis, which is most often caused by Rhizopus oryzae. Although the deferoxamine siderophore is not secreted by Mucorales, previous studies established that Rhizopus species utilize iron from ferrioxamine (iron-rich form of deferoxamine). Here we determined that the CBS domain proteins of Fob1 and Fob2 act as receptors on the cell surface of R. oryzae during iron uptake from ferrioxamine. Fob1 and Fob2 cell surface expression was induced in the presence of ferrioxamine and bound radiolabeled ferrioxamine. A R. oryzae strain with targeted reduced Fob1/Fob2 expression was impaired for iron uptake, germinating, and growing on medium with ferrioxamine as the sole source of iron. This strain also exhibited reduced virulence in a deferoxamine-treated, but not the diabetic ketoacidotic (DKA), mouse model of mucormycosis. The mechanism by which R. oryzae obtains iron from ferrioxamine involves the reductase/permease uptake system since the growth on ferrioxamine supplemented medium is associated with elevated reductase activity and the use of the ferrous chelator bathophenanthroline disulfonate abrogates iron uptake and growth on medium supplemented with ferrioxamine as a sole source of iron. Finally, R. oryzae mutants with reduced copies of the high affinity iron permease (FTR1) or with decreased FTR1 expression had an impaired iron uptake from ferrioxamine in vitro and reduced virulence in the deferoxamine-treated mouse model of mucormycosis. These two receptors appear to be conserved in Mucorales, and can be the subject of future novel therapy to maintain the use of deferoxamine for treating iron-overload.

Additional Information

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Received: May 22, 2014; Accepted: March 31, 2015; Published: May 14, 2015. The authors gratefully acknowledge the technical assistance of May Abdallah in isolating the putative ferrioxamine receptors and Hongku Lee in helping with the animal studies. We also would like to thank Pryia Uppuluri and Sameh Soliman for discussions and critical review of the manuscript. Research described in this manuscript was conducted at the research facilities of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. This work was supported by Public Health Service grants R01 AI063503 to ASI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Author Contributions: Conceived and designed the experiments: ML ASI JEE. Performed the experiments: ML LL TG GL SWF TFC ASI. Analyzed the data: ML LL SWF ASI. Contributed reagents/materials/analysis tools: CDS. Wrote the paper: ASI ML. Revised the manuscript: CDS JEE. The authors have declared that no competing interests exist. Data Availability Statement: All relevant data are within the paper and its Supporting Information files.

Attached Files

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Supplemental Material - ppat.1004842.s001.tif

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Supplemental Material - ppat.1004842.s007.docx

Supplemental Material - ppat.1004842.s008.docx


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August 22, 2023
August 22, 2023