|LIU, MINGFU - Los Angeles Biomedical Research Institute|
|GEBREMARIAM, TECLEGIORGIS - Los Angeles Biomedical Research Institute|
|LUO, GUANPINGSHENG - Los Angeles Biomedical Research Institute|
|Skory, Christopher - Chris|
|FRENCH, SAMEUL - Los Angeles Biomedical Research Institute|
|EDWARDS, JR., JOHN - Los Angeles Biomedical Research Institute|
|IBRAHIM, ASHRAF - Los Angeles Biomedical Research Institute|
Submitted to: PLoS Pathogens
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/31/2015
Publication Date: 5/14/2015
Publication URL: http://handle.nal.usda.gov/10113/62187
Citation: Liu, M., Lin, L., Gebremariam, T., Luo, G., Skory, C.D., French, S.W., Chou, T.F., Edwards, Jr., J.E., Ibrahim, A.S. 2015. Fob1 and Fob2 proteins are virulence determinants of Rhizopus oryzae via facilitating iron uptake from ferrioxamine. PLoS Pathogens. 11(5):e100482. DOI: 10.1371/journal.ppat.1004842.
Interpretive Summary: The filamentous fungus Rhizopus oryzae is used in numerous industrial/food applications and is an organism that is generally regarded as being safe. However, it is the most prevalent cause of mucormycosis, a life-threatening infection that usually afflicts patients with debilitated immune systems or those with specific underlying abnormalities. Uptake of iron by the fungus appears to be closely linked to the infection process and considerable research has focused on this mechanism. In this work, we identify two proteins in Rhizopus that act as receptors to facilitate iron uptake by the fungus. We also show that these receptors are required for full virulence of the fungus during infections. This work is expected to enhance current treatment options and significantly increase the likelihood of survival for this type of infection.
Technical Abstract: Dialysis patients with chronic renal failure receiving deferoxamine for treating iron overload are uniquely predisposed for mucormycosis. Although 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, the most common cause of mucormycosis, during iron uptake from ferrioxamine. Fob1 and Fob2 cell surface expression was induced in the presence of ferrioxamine and bound radiolabeled ferrioxamine. A mutant of R. oryzae with 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 bipyridyl abrogates iron uptake and growth on medium supplemented with ferrioxamine as a sole source of iron. Finally, a R. oryzae mutant with reduced copies of the high affinity iron permease (FTR1) 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 at least another two Mucorales (i.e. Mucor circinelloides and Mortierella verticillata) and can be the subject of future novel therapy to maintain the use of deferoxamine for treating iron-overload.