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Title: The High Affinity Iron Permease is a Key Virulence Factor Required for Rhizopus oryzae Pathogenesis

item IBRAHIM, ASHRAF - University Of California
item GEBREMARIAM, TECLEGIORGIS - University Of California
item LIN, LIN - University Of California
item LUO, GUANPINKSHENG - University Of California
item HUSSEINY, MOHAMED - University Of California
item Skory, Christopher - Chris
item FU, YUE - University Of California
item FRENCH, SAMUEL - University Of California
item EDWARDS, JR., JOHN - University Of California
item SPELLBERG, BRAD - University Of California

Submitted to: Molecular Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/17/2010
Publication Date: 6/9/2010
Citation: Ibrahim, A.S., Gebremariam, T., Lin, L., Husseiny, M.I., Skory, C.D., Fu, Y., French, S.W., Edwards, Jr, J.E., Spellberg, B. 2010. The high affinity iron permease is a key virulence factor required for Rhizopus oryzae pathogenesis. Molecular Microbiology. 77(3):587-604.

Interpretive Summary: This research demonstrates the importance of a protein involved in iron uptake in the fungus Rhizopus, which has broad interest to the industrial, agricultural, and medical community. Isolates of this organism have the ability to synthesize enzymes and chemicals (e.g. lactic acid or fumaric) on a commercial scale, but are also responsible for food and agricultural crop spoilage and opportunistic (i.e. will not affect healthy individuals) infections. Rhizopus can only grow if it is able to obtain iron from its surroundings using specific transporters that bring the iron into the cell. Understanding how this process works is critical to controlling growth of the organism. This work focused on a specific transport protein called rFTR1 that appears to be the principal mechanism for importing iron. Deletion of the gene required to make this protein prevented growth of the fungus. Additionally, decreasing the amount of this protein had a direct correlation on the ability to take up iron. The results of this study provide valuable information that will be of interest to clinicians and scientists; and are expected to provide new targets for controlling the growth of this important fungus.

Technical Abstract: Rhizopus oryzae is the most common cause of mucormycosis, an angioinvasive fungal infection that causes a >/=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 (rFTR1) is required for R. oryzae iron transport in iron-depleted environments, such as those found in the host during infection. To define its role in R. oryzae virulence, we sought to abrogate the function of rFTR1 by gene disruption or by RNA interference. Here we demonstrate that rFTR1 is required for full virulence of R. oryzae in mice. We show that rFTR1 is expressed during infection in diabetic ketoacidotic (DKA) mice. In addition, rFTR1 could be disrupted by double cross-over homologous recombination, but multinucleated R. oryzae could not be forced to segregate to a homokaryotic null allele, regardless of the availability of extracellular iron. Nevertheless, a reduction in the relative copy number of functional rFTR1 demonstrated that it was indispensible for growth, especially in iron-depleted environments. Reduction of the relative copy number of rFTR1 or inhibition of rFTR1 expression compromised the ability of R. oryzae to acquire iron in vitro and reduced its virulence in DKA mice. Importantly, passive immunization with anti-rFtr1p immune sera significantly protected DKA mice from infection with R. oryzae. Thus rFTR1 is a crucial virulence factor for R. oryzae, and passive immunotherapy against rFtr1p is a promising strategy to improve outcomes of these deadly infections.