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

Boelaert, Johan R.; Locht, M. de; Cutsem, J. Van; Kerrels, Véronique; Cantinieaux, Brigitte; Verdonck, Ann; Landuyt, H. W. Van; Schneider, Yves‐Jacques

doi:10.1172/jci116419

Cited by 307 publications

(280 citation statements)

References 35 publications

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“…19 A clinical example of this is the increased rate of zygomycosis among dialysis patients treated with desferrioxamine because iron bound to desferrioxamine is efficiently used as an iron source by some species of zygomycetes. 20 We saw an association between Aspergillus and iron overload, more clearly with autografts than with allografts. In allograft patients, other potentially more important variables such as acute GVHD, immunosuppression, CMV, and steroid treatment may mask any effect of iron.…”

Section: Discussionmentioning

confidence: 87%

Frequent severe liver iron overload after stem cell transplantation and its possible association with invasive aspergillosis

Altés

Remacha

Sarda

et al. 2004

Bone Marrow Transplant

119

106

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Summary:Iron overload is associated with free radical generation and tissue damage. Our main objective was to ascertain the frequency and severity of iron overload in a group of 59 patients who died after conventional-intensity autologous (n ¼ 24) or allogeneic (n ¼ 35) haematopoietic stem cell transplantation (HSCT). A second objective was to investigate associations between liver-iron concentration and causes of transplant-related mortality. The median age was 41 years (range, 19-66), 41 were males and 18 females. In total, 26 patients had acute leukaemia or MDS, 10 CML, 17 lymphoma, four myeloma and two aplastic anaemia. The median hepatic iron concentration (HIC) was 138 lmol/g dry weight (7.7 mg/g; range 31-631 lmol/g). In total, 4/32 (12%) patients with HIC o150 lmol/g and 10/27 (37%) with hepatic iron X150 lmol/g showed invasive aspergillosis at autopsy (P ¼ 0.035). This was significant in multivariate analysis (RR 9.0; 95% CI 1.6-50.3, P ¼ 0.012). In conclusion, severe iron overload is frequent in patients who die following HSCT and is associated with invasive aspergillosis.

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Section: Discussionmentioning

confidence: 87%

Frequent severe liver iron overload after stem cell transplantation and its possible association with invasive aspergillosis

Altés

Remacha

Sarda

et al. 2004

Bone Marrow Transplant

119

106

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“…Iron overload was also associated with fungal infection in liver transplant (5), and in hematologic malignancies (7). Interestingly, patients being treated for iron overload with desferroxamine, a siderophore made by Streptomyces, are at increased risk for mucormycosis (56). This may be explained by the observation that Rhizopus microsporus, one of the causes of mucormycosis, is able to acquire iron from the iron-chelated form of the bacterial siderophore, ferroxamine (57).…”

Section: Discussionmentioning

confidence: 99%

Human Polymorphonuclear Leukocytes Inhibit Aspergillus fumigatus Conidial Growth by Lactoferrin-Mediated Iron Depletion

Zarember

Sugui

Chang

et al. 2007

The Journal of Immunology

171

137

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Aspergillus fumigatus, a common mold, rarely infects humans, except during prolonged neutropenia or in cases of chronic granulomatous disease (CGD), a primary immunodeficiency caused by mutations in the NADPH oxidase that normally produces fungicidal reactive oxygen species. Filamentous hyphae of Aspergillus are killed by normal, but not CGD polymorphonuclear leukocytes (PMN); however, the few studies on PMN-mediated host defenses against infectious conidia (spores) of this organism have yielded conflicting results, some showing that PMN do not inhibit conidial growth, with others showing that they do, most likely using reactive oxygen species. Given that CGD patients are exposed daily to hundreds of viable A. fumigatus conidia, yet considerable numbers of them survive years without infection, we reasoned that PMN use ROS-independent mechanisms to combat Aspergillus. We show that human PMN from both normal controls and CGD patients are equipotent at arresting the growth of Aspergillus conidia in vitro, indicating the presence of a reactive oxygen species-independent factor(s). Cell-free supernatants of degranulated normal and CGD neutrophils both suppressed fungal growth and were found to be rich in lactoferrin, an abundant PMN secondary granule protein. Purified iron-poor lactoferrin at concentrations occurring in PMN supernatants (and reported in human mucosal secretions in vivo) decreased fungal growth, whereas saturation of lactoferrin or PMN supernatants with iron, or testing in the presence of excess iron in the form of ferritin, completely abolished activity against conidia. These results demonstrate that PMN lactoferrin sequestration of iron is important for host defense against Aspergillus.

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“…Patients with elevated available serum iron, such as DKA patients (11) or those treated with deferoxamine (an iron siderophore that provides Rhizopus with exogenous iron) (12), are uniquely predisposed to developing mucormycosis. Furthermore, the iron chelator deferasirox, which reduces available serum iron, is effective in treating experimental hematogenously disseminated mucormycosis (13).…”

Section: Grp78 Binds To Mucorales Germlings But Not Sporesmentioning

confidence: 99%

The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice

Liu¹,

Spellberg²,

Phan³

et al. 2010

J. Clin. Invest.

273

314

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Mucormycosis is a fungal infection of the sinuses, brain, or lungs that causes a mortality rate of at least 50% despite first-line therapy. Because angioinvasion is a hallmark of mucormycosis infections, we sought to define the endothelial cell receptor(s) for fungi of the order Mucorales (the fungi that cause mucormycosis). Furthermore, since patients with elevated available serum iron, including those with diabetic ketoacidosis (DKA), are uniquely susceptible to mucormycosis, we sought to define the role of iron and glucose in regulating the expression of such a receptor. Here, we have identified glucose-regulated protein 78 (GRP78) as what we believe to be a novel host receptor that mediates invasion and damage of human endothelial cells by Rhizopus oryzae, the most common etiologic species of Mucorales, but not Candida albicans or Aspergillus fumigatus. Elevated concentrations of glucose and iron, consistent with those seen during DKA, enhanced GRP78 expression and the resulting R. oryzae invasion and damage of endothelial cells in a receptor-dependent manner. Mice with DKA, which have enhanced susceptibility to mucormycosis, exhibited increased expression of GRP78 in sinus, lungs, and brain compared with normal mice. Finally, GRP78-specific immune serum protected mice with DKA from mucormycosis. These results suggest a unique susceptibility of patients with DKA to mucormycosis and provide a foundation for the development of new therapeutic interventions for these deadly infections.

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

Cited by 307 publications

References 35 publications

Frequent severe liver iron overload after stem cell transplantation and its possible association with invasive aspergillosis

Frequent severe liver iron overload after stem cell transplantation and its possible association with invasive aspergillosis

Human Polymorphonuclear Leukocytes Inhibit Aspergillus fumigatus Conidial Growth by Lactoferrin-Mediated Iron Depletion

The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice

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