high affinity iron permease is a key virulence factor required for Rhizopus oryzae pathogenesis

• Published in: Molecular microbiology Vol. 77; no. 3; pp. 587 - 604
• Main Authors: Ibrahim, Ashraf S, Gebremariam, Teclegiorgis, Lin, Lin, Luo, Guanpingsheng, Husseiny, Mohamed I, Skory, Christopher D, Fu, Yue, French, Samuel W, Edwards, John E. Jr, Spellberg, Brad
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.08.2010; Blackwell Publishing Ltd; Blackwell
• Subjects: animal disease models; Animals; Biological and medical sciences; diabetic ketoacidosis; Diabetic Ketoacidosis - microbiology; Fundamental and applied biological sciences. Psychology; Fungal infections; Fungal plant pathogens; fungal proteins; Fungal Proteins - genetics; Fungal Proteins - metabolism; Fungi; Gene expression; human diseases; human health; Humans; Iron; Iron - metabolism; iron permease; Male; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Mice; Mice, Inbred BALB C; Microbiology; Miscellaneous; Mucormycosis - microbiology; Mycology; mycoses; Pathogenesis; pathogenicity; Phytopathology. Animal pests. Plant and forest protection; Protein Binding; Rhizopus - enzymology; Rhizopus - genetics; Rhizopus - pathogenicity; Rhizopus oryzae; Rodents; transport proteins; Virulence Factors - genetics; Virulence Factors - metabolism; Fungi; Zygomycota; Rhizopus oryzae; Plant pathogen; Pathogenesis; Permease; Virulence; Iron
• ISSN: 0950-382X; 1365-2958
• DOI: 10.1111/j.1365-2958.2010.07234.x

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.