title: The high affinity iron permease is a key virulence factor required for Rhizopus oryzae pathogenesis.
abstract: Rhizopus oryzae is the most common cause of mucormycosis, an angioinvasive fungal infection that causes more then 50% mortality rate despite first-line therapy. Clinical and animal model data clearly demonstrate that the presence of elevated available serum iron predisposes the host to mucormycosis. The high affinity iron permease gene (FTR1) is required for R. oryzae iron transport in iron-depleted environments. Here we demonstrate that FTR1 is required for full virulence of R. oryzae in mice. We show that FTR1 is expressed during infection in diabetic ketoacidosis (DKA) mice. In addition, we disrupted FTR1 by double cross-over homologous recombination, but multinucleated R. oryzae could not be forced to segregate to a homokaryotic null allele. Nevertheless, a reduction of the relative copy number of FTR1 and inhibition of FTR1 expression by RNAi compromised the ability of R. oryzae to acquire iron in vitro and reduced its virulence in DKA mice. Importantly, passive immunization with anti-Ftr1p immune sera protected DKA mice from infection with R. oryzae. Thus, FTR1 is a virulence factor for R. oryzae, and anti-Ftr1p passive immunotherapy deserves further evaluation as a strategy to improve outcomes of deadly mucormycosis.
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-University of California Los Angeles (UCLA) Medical Center, Torrance, CA, USA. ibrahim@labiomed.org
authors.forename: Ashraf S
authors.initials: AS
authors.lastname: Ibrahim
authors.forename: Teclegiorgis
authors.initials: T
authors.lastname: Gebremariam
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Guanpingsheng
authors.initials: G
authors.lastname: Luo
authors.forename: Mohamed I
authors.initials: MI
authors.lastname: Husseiny
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Skory
authors.forename: Yue
authors.initials: Y
authors.lastname: Fu
authors.forename: Samuel W
authors.initials: SW
authors.lastname: French
authors.forename: John E
authors.initials: JE
authors.lastname: Edwards
authors.forename: Brad
authors.initials: B
authors.lastname: Spellberg
mesh_terms: D000818:Animals; D016883:Diabetic Ketoacidosis / Q000382:microbiology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009091:Mucormycosis / Q000382:microbiology*; D011485:Protein Binding; D012233:Rhizopus / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D037521:Virulence Factors; D007501:Iron