Mucormycosis, most commonly caused by Rhizopus oryzae, is a life-threatening infection that occurs in patients immunocompromised by diabetic ketoacidosis (DKA), neutropenia, corticosteroid use, and/or increased serum iron. Because of the rising prevalence of these risk factors, the incidence of mucormycosis has risen. Despite disfiguring surgery and aggressive antifungal therapy, the mortality of mucormycosis remains >40%, and approaches 100% in patients with disseminated disease. Clearly new strategies to prevent and treat mucormycosis are needed. Clinical hallmarks of R. oryzae infection include its remarkable angiotropism and the hypersusceptibility of patients with increased available serum iron to this infection. Patients with elevated levels of available serum iron such as those with DKA or who have received deferoxamine are uniquely susceptible to mucormycosis, but not other fungal infections. Deferoxamine acts as a xeno-siderophore which supplies previously unavailable iron to the fungus. We have shown that iron chelation with chelators that are not utilized by the fungus to obtain iron protects mice from infection with R. oryzae. We also found that the high affinity iron permease (Ftr1p) is critical to the ability of the fungus to obtain iron during infection. Equally important is our recent identification of the iron-regulated GRP78 as a host cell receptor to which R. oryzae binds during the process of invading endothelial cells, a step required for angioinvasion. Finally, we found that anti-Ftr1p or anti-Grp78 antibodies markedly, but not completely, protected DKA mice from infection with R. oryzae. These findings underscore the critical role of iron and invasion of vascular endothelial cells in the organism's virulence strategies. We propose to build on these exciting data to further characterize fungal and host targets that are involved in iron uptake and/or regulated by iron. Our goal is to develop multiple immunotherapeutic strategies that will prove to be synergistic in preventing and/or treating lethal mucormycosis. We will achieve this goal by identifying the fungal ligand involved in mediating binding of R. oryzae to endothelial cell GRP78. We will continue identifying host receptors, other than GRP78, that promote adherence to and/or invasion of and subsequent injury to endothelial cells by R. oryzae. Additionally, we will study the effect of physiological conditions, including iron, on the pattern of GRP78 expression in vivo. Finally, we will identify fungal receptors which act upstream of Ftr1p in mediating iron uptake from the host. Achieving these specific aims will further define the role of iron in the establishment and progression of mucormycosis and define possible novel therapeutic strategies that can be applied concurrently against the disease.

Public Health Relevance

Iron is essential for the growth of Rhizopus oryzae, a fungus that causes life-threatening infections in patients suffering from high levels of iron in their blood. Current treatment options for mucormycosis are inadequate, and fail in 40% or more of infected patients. We propose to identify targets that are involved in aiding the fungus in obtaining iron and/or regulated by iron to use in the future design of therapeutic strategies to prevent or treat these lethal infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
La Biomed Research Institute/ Harbor UCLA Medical Center
United States
Zip Code
Gebremariam, Teclegiorgis; Lin, Lin; Liu, Mingfu et al. (2016) Bicarbonate correction of ketoacidosis alters host-pathogen interactions and alleviates mucormycosis. J Clin Invest 126:2280-94
Chibucos, Marcus C; Soliman, Sameh; Gebremariam, Teclegiorgis et al. (2016) An integrated genomic and transcriptomic survey of mucormycosis-causing fungi. Nat Commun 7:12218
Bellanger, Anne-Pauline; Tatara, Alexander M; Shirazi, Fazal et al. (2016) Statin Concentrations Below the Minimum Inhibitory Concentration Attenuate the Virulence of Rhizopus oryzae. J Infect Dis 214:114-21
Liu, Mingfu; Lin, Lin; Gebremariam, Teclegiorgis et al. (2015) Fob1 and Fob2 Proteins Are Virulence Determinants of Rhizopus oryzae via Facilitating Iron Uptake from Ferrioxamine. PLoS Pathog 11:e1004842
Gebremariam, Teclegiorgis; Wiederhold, Nathan P; Fothergill, Annette W et al. (2015) VT-1161 Protects Immunosuppressed Mice from Rhizopus arrhizus var. arrhizus Infection. Antimicrob Agents Chemother 59:7815-7
Mendoza, Leonel; Vilela, Raquel; Voelz, Kerstin et al. (2015) Human Fungal Pathogens of Mucorales and Entomophthorales. Cold Spring Harb Perspect Med 5:
Shirazi, Fazal; Kontoyiannis, Dimitrios P; Ibrahim, Ashraf S (2015) Iron starvation induces apoptosis in Rhizopus oryzae in vitro. Virulence 6:121-6
Chibucos, Marcus C; Etienne, Kizee A; Orvis, Joshua et al. (2015) The genome sequence of four isolates from the family Lichtheimiaceae. Pathog Dis 73:
Luo, G; Spellberg, B; Gebremariam, T et al. (2014) Combination therapy with iron chelation and vancomycin in treating murine staphylococcemia. Eur J Clin Microbiol Infect Dis 33:845-51
Gebremariam, Teclegiorgis; Liu, Mingfu; Luo, Guanpingsheng et al. (2014) CotH3 mediates fungal invasion of host cells during mucormycosis. J Clin Invest 124:237-50

Showing the most recent 10 out of 46 publications