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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI063503-10
Application #
8889496
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2006-02-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
10
Fiscal Year
2015
Total Cost
$354,925
Indirect Cost
$104,925
Name
La Biomed Research Institute/ Harbor UCLA Medical Center
Department
Type
DUNS #
069926962
City
Torrance
State
CA
Country
United States
Zip Code
90502
Mamouei, Zeinab; Alqarihi, Abdullah; Singh, Shakti et al. (2018) Alexidine Dihydrochloride Has Broad-Spectrum Activities against Diverse Fungal Pathogens. mSphere 3:
Watkins, Tonya N; Gebremariam, Teclegiorgis; Swidergall, Marc et al. (2018) Inhibition of EGFR Signaling Protects from Mucormycosis. MBio 9:
Andrianaki, Angeliki M; Kyrmizi, Irene; Thanopoulou, Kalliopi et al. (2018) Iron restriction inside macrophages regulates pulmonary host defense against Rhizopus species. Nat Commun 9:3333
Baldin, Clara; Soliman, Sameh S M; Jeon, Heewon H et al. (2018) PCR-Based Approach Targeting Mucorales-Specific Gene Family for Diagnosis of Mucormycosis. J Clin Microbiol 56:
Shumilov, Evgenii; Bacher, Ulrike; Perske, Christina et al. (2018) In Situ Validation of the Endothelial Cell Receptor GRP78 in a Case of Rhinocerebral Mucormycosis. Antimicrob Agents Chemother 62:
Skiada, A; Lass-Floerl, C; Klimko, N et al. (2018) Challenges in the diagnosis and treatment of mucormycosis. Med Mycol 56:93-101
Ibrahim, Ashraf S; Voelz, Kerstin (2017) The mucormycete-host interface. Curr Opin Microbiol 40:40-45
Gebremariam, Teclegiorgis; Wiederhold, Nathan P; Alqarihi, Abdullah et al. (2017) Monotherapy or combination therapy of isavuconazole and micafungin for treating murine mucormycosis. J Antimicrob Chemother 72:462-466
Gebremariam, Teclegiorgis; Alkhazraji, Sondus; Baldin, Clara et al. (2017) Prophylaxis with Isavuconazole or Posaconazole Protects Immunosuppressed Mice from Pulmonary Mucormycosis. Antimicrob Agents Chemother 61:
Gebremariam, Teclegiorgis; Alkhazraji, Sondus; Lin, Lin et al. (2017) Prophylactic Treatment with VT-1161 Protects Immunosuppressed Mice from Rhizopus arrhizus var. arrhizus Infection. Antimicrob Agents Chemother 61:

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