Effects of iron and desferrioxamine on Rhizopus infection

Abstract

To investigate the association among iron, desferrioxamine, and a Rhizopus infection, the influence of iron and/or desferrioxamine on experimental mucormycosis in mice was examined. All mice pretreated with iron, desferrioxamine, or a combination of iron and desferrioxamine died within 5 days after the inoculation of R. oryzae. In the mice fungal lesions were observed in the brain which resembled human cerebral mucormycosis. By contrast, the mortality in the control mice with R. oryzae was 20% through the 3-week experimental period. Therefore, it was demonstrated that iron as well as desferrioxamine administration markedly promotes the growth of R. oryzae. The increased susceptibility to R. oryzae was considered to be due to increased serum iron in the animals pretreated with iron only; however, pretreatment with desferrioxamine did not affect the amount of serum ion. Thus, the data suggest that desferrioxamine acts as a siderophore to R. oryzae and exerts an adverse effect on mucormycosis. This study has shown that the presence of iron and desferrioxamine enhances the virulence and pathogenicity of R. oryzae by serving as a growth factor.

Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies.

“…A similar aggravation of experimental mucormycosis by DFO was found in the mouse by an independent group of investigators (29). In uninfected animals, DFO at the same dosage did not influence survival (3).…”

“…Indeed, pharmacokinetic changes in uremia lead to a sixfold prolongation ofthe elimination halftime and a 4.9-fold increase in the area under the concentration-time curve for Fe.DFO in dialysis patients, when compared with subjects with normal renal function, after one single DFO administration (38). 44 In vivo pretreatment ofmice with aluminum salts has no effect upon the susceptibility to Rhizopus infection (39), whereas pretreatment with iron salts aggravates the infection (3,29). This supports the idea that the slight effect of Al.DFO in vitro could be due to formation of some Fe.DFO.…”

Mucormicosis en Pediatría

“…22 A su vez, la desferoxamina, utilizada como agente quelante del Fe +++ en sujetos que tienen depósitos tisulares patológicos del metal (por ejemplo pacientes con hemocromatosis, politransfundidos o hemodializados), desprende y captura este Fe +++ para eliminarlo por vía fecal y urinaria, lo que expone al paciente colonizado a desarrollar enfermedad. Además el hongo es capaz de utilizar la desferoxamina como un sideróforo en su propio beneficio incrementando su viabilidad 23,24 . No se han descrito toxinas propias para este grupo de hongos.…”

The iron chelator deferasirox protects mice from mucormycosis through iron starvation

“…Based on this role of iron sequestration in innate immunity, recent interest has been generated in the possibility of utilizing iron chelation therapy as a treatment for infectious diseases. Mucormycosis is a particularly promising target for iron chelation therapy given the exceptional iron requirement for growth and pathogenicity of Mucorales (12)(13)(14)(15). For example, it is likely that diabetic ketoacidosis and other systemic acidoses predispose patients to developing mucormycosis by inducing dissociation of iron from sequestering proteins, resulting in elevated available serum iron (2,16,17).…”

“…However, while deferoxamine is an iron chelator from the perspective of the human host, it serves as a xenosiderophore to Mucorales, which are able to specifically bind to deferoxamineiron complexes, strip the iron from the chelator through an energy-dependent reductive process, and facilitate iron uptake (12,18). Furthermore, administration of deferoxamine worsens survival of animals with mucormycosis (12)(13)(14)(15). In contrast, other iron chelators do not act as iron siderophores for Mucorales.…”