Mucormycosis is a life-threatening infection that occurs in patients immunocompromised by diabetic ketoacidosis, neutropenia, steroid use, and/or increased serum iron. Because of the rising prevalence of risk factors, the incidence of mucormycosis has dramatically increased (1300% over 15 years according to one source). Despite disfiguring surgery and aggressive antifungal therapy, the mortality of mucormycosis remains >50%, and approaches 100% in patients with disseminated disease. Clearly new strategies to prevent and treat mucormycosis are urgently needed. Clinical hallmarks of infection by Rhizopus oryzae, the most common cause of mucormycosis, include the unique susceptibility of patients with increased available serum iron, the propensity of the organism to invade blood vessels, and defective phagocytic function, which we hypothesize to be, at least in part, a result of iron toxicity. These clinical hallmarks underscore the critical role of iron metabolism, as well as interactions with endothelial cells lining blood vessels, in the organism's virulence strategy. We have found that R. oryzae damages endothelial cells in vitro and this process is dependent on iron. Additionally, we have cloned the R. oryzae high affinity iron permease (rFTR1) which scavenges iron from iron-depleted environments such as is found in the host. Finally we have developed clinically relevant models of infection in diabetic ketoacidotic mice. We hypothesize that iron uptake, and specifically rFTR1, is essential for R. oryzae to cause infection. To test this hypothesis, we propose to: 1) characterize the mechanism(s) by which iron regulates R. oryzae- induced endothelial cell injury;2) construct an isogenic rftrl null mutant and its corresponding rFTR1 complemented strain jn R. oryzae by site directed mutagenesis;3) compare the pathogenicity of the generated rftrl to that of the wild-type and rFTR1 complemented strains in our in vitro and in vivo models of infection;and 4) elucidate the role of iron in regulating the innate host response to R. oryzae. Accomplishing these specific aims will define the role of the central elements affecting the establishment and progression of mucormycosis as it relates to iron uptake. Ultimately, a superior understanding of the pathogenesis of mucormycosis will enable development of novel therapies for this disease. Completion of the proposed studies will enable investigation of treatments that block R. oryzae uptake of iron.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI063503-05
Application #
7754427
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2006-02-01
Project End
2011-07-14
Budget Start
2010-02-01
Budget End
2011-07-14
Support Year
5
Fiscal Year
2010
Total Cost
$269,001
Indirect Cost
Name
La Biomed Research Institute/ Harbor UCLA Medical Center
Department
Type
DUNS #
069926962
City
Torrance
State
CA
Country
United States
Zip Code
90502
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; Lin, Lin et al. (2017) Prophylactic Treatment with VT-1161 Protects Immunosuppressed Mice from Rhizopus arrhizus var. arrhizus Infection. Antimicrob Agents Chemother 61:
Gebremariam, Teclegiorgis; Alkhazraji, Sondus; Baldin, Clara et al. (2017) Prophylaxis with Isavuconazole or Posaconazole Protects Immunosuppressed Mice from Pulmonary Mucormycosis. Antimicrob Agents Chemother 61:
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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
Liu, Hong; Lee, Mark J; Solis, Norma V et al. (2016) Aspergillus fumigatus CalA binds to integrin ?5?1 and mediates host cell invasion. Nat Microbiol 2:16211
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
Chibucos, Marcus C; Etienne, Kizee A; Orvis, Joshua et al. (2015) The genome sequence of four isolates from the family Lichtheimiaceae. Pathog Dis 73:
Shirazi, Fazal; Kontoyiannis, Dimitrios P; Ibrahim, Ashraf S (2015) Iron starvation induces apoptosis in Rhizopus oryzae in vitro. Virulence 6:121-6

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