title: Fob1 and Fob2 Proteins Are Virulence Determinants of Rhizopus oryzae via Facilitating Iron Uptake from Ferrioxamine.
abstract: 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.
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center, Torrance, California, United States of America.
authors.forename: Mingfu
authors.initials: M
authors.lastname: Liu
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center, Torrance, California, United States of America; David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center, Torrance, California, United States of America.
authors.forename: Teclegiorgis
authors.initials: T
authors.lastname: Gebremariam
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center, Torrance, California, United States of America.
authors.forename: Guanpingsheng
authors.initials: G
authors.lastname: Luo
authors.affiliation: National Center for Agricultural Utilization Research, United States Department of Agriculture (USDA), Peoria, Illinois, United States of America.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Skory
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center, Torrance, California, United States of America; Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: French
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Harbor-University of California, Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Torrance, California, United States of America.
authors.forename: Tsui-Fen
authors.initials: TF
authors.lastname: Chou
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center, Torrance, California, United States of America; David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: John E
authors.initials: JE
authors.lastname: Edwards
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center, Torrance, California, United States of America; David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Ashraf S
authors.initials: AS
authors.lastname: Ibrahim
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003676:Deferoxamine / Q000378:metabolism*; D005290:Ferric Compounds / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D009091:Mucormycosis / Q000188:drug therapy* / Q000382:microbiology; D012233:Rhizopus / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D017262:Siderophores / Q000378:metabolism; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D005290:Ferric Compounds; C000606546:Fob2 protein, S cerevisiae; D007502:Iron Chelating Agents; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D029701:Saccharomyces cerevisiae Proteins; D017262:Siderophores; D037521:Virulence Factors; C002577:ferrioxamine B; D007501:Iron; D003676:Deferoxamine