Iron and Infection: The Clinical Evidence

Sj, Oppenheimer

doi:10.1111/apa.1989.78.s361.53

Cited by 41 publications

(24 citation statements)

References 83 publications

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“…26 We selected 250 mM as a representation of iron overload that may occur due to hemochromatosis or severe liver disease in humans. 21,27,28 We observed an increased LC3-II to LC3-I ratio after iron treatment, indicating accumulation of autophagosomes (Fig. 1A).…”

Section: Iron Treatment Induces Ferritinophagymentioning

confidence: 81%

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Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

Bauckman

Mysorekar

2016

Autophagy

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Autophagy is a cellular recycling pathway, which in many cases, protects host cells from infections by degrading pathogens. However, uropathogenic Escherichia coli (UPEC), the predominant cause of urinary tract infections (UTIs), persist within the urinary tract epithelium (urothelium) by forming reservoirs within autophagosomes. Iron is a critical nutrient for both host and pathogen, and regulation of iron availability is a key host defense against pathogens. Iron homeostasis depends on the shuttling of iron-bound ferritin to the lysosome for recycling, a process termed ferritinophagy (a form of selective autophagy). Here, we demonstrate for the first time that UPEC shuttles with ferritin-bound iron into the autophagosomal and lysosomal compartments within the urothelium. Iron overload in urothelial cells induces ferritinophagy in an NCOA4-dependent manner causing increased iron availability for UPEC, triggering bacterial overproliferation and host cell death. Addition of even moderate levels of iron is sufficient to increase and prolong bacterial burden. Furthermore, we show that lysosomal damage due to iron overload is the specific mechanism causing host cell death. Significantly, we demonstrate that host cell death and bacterial burden can be reversed by inhibition of autophagy or inhibition of iron-regulatory proteins, or chelation of iron. Together, our findings suggest that UPEC persist in host cells by taking advantage of ferritinophagy. Thus, modulation of iron levels in the bladder may provide a therapeutic avenue to controlling UPEC persistence, epithelial cell death, and recurrent UTIs.

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Section: Iron Treatment Induces Ferritinophagymentioning

confidence: 81%

“…27,28,54,55 In both of these scenarios, excess free iron is present leading to opportunistic pathogenic burden. A number of case studies have even documented E. coli-associated bacteremia in hemochromatosis patients.…”

Section: Discussionmentioning

confidence: 99%

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

Bauckman

Mysorekar

2016

Autophagy

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“…Iron is a known trophic factor for several pathogenic bacteria and there has also been concern that iron supplementation of breast-fed infants may saturate human milk lactoferrin, thus diminishing its anti-infective properties (75). Parenteral iron therapy has been associated with the exacerbation of malaria and neonatal sepsis (76). For these reasons, it has been suggested that iron forti cation and supplementation may increase the incidence of gastroenteritis and other infections in infants.…”

Section: Safety Aspectsmentioning

confidence: 99%

Iron-deficiency anaemia during the first two years of life

Domellöf

Hernell²

2002

Food & Nutrition Research

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A bstractIron-de ciency anaemia (IDA) is a global public health problem, affecting an estimated 51% of children below 4 years of age in developing countries and 12% in developed countries. Owing to rapid body growth and a depletion of neonatal iron stores, iron requirements during late infancy are higher than during any other period of life. There is a well-known association between IDA and delayed neurodevelopment in infants and young children. Early weaning to cow's milk or formula unforti ed with iron is known to increase the risk for IDA in this age group. Iron forti cation of common infant foods is recommended in many countries. Iron supplements are often recommended for infants who are breast-fed for longer than 4 -6 months and who do not consume adequate amounts of iron-forti ed complementary foods. The scienti c bases for these recommendations are discussed in this review, as are safety aspects, and the diagnostic criteria for IDA in infants and young children are critically examined.

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“…The availability of iron plays a critical role in host-parasite interactions (13,28,29,41,42). Iron is required for the growth of nearly all forms of bacterial, fungal, protozoal, plant, and animal cells (43,44).…”

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confidence: 99%

Iron chelators as therapeutic agents against Pneumocystis carinii

Weinberg

1994

Antimicrob Agents Chemother

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Iron plays a critical role in host-parasite interactions, and iron chelators have been demonstrated to serve as effective adjunct therapeutic agents against malaria. The effects of the parenteral iron chelator deferoxamine (DFO) on the growth of rat-derived Pneumocystis carinii were studied in a human fibroblast cell culture model and in two in vivo models of experimental infection. In addition, the effects of the investigational oral iron chelator CP20 and its 3-hydroxypyridin-4-one analogs CP51, CP94, and CP96 on the growth of P. carinii in vitro were assessed. DFO suppressed the growth of P. carinii in vitro in a dose-dependent manner, and daily injections of DFO markedly reduced the intensity of P. carinii infection in both mice and rats. Cell cultures treated with iron chelators that are administered orally to humans also showed substantial P. carinii growth inhibition. Reduction of P. carinii numbers after iron chelator therapy correlated with alterations in P. carinii morphology, as viewed by transmission electron microscopy. Since the use of current anti-P. carinii drugs is limited by toxicity or incomplete efficacy, or both, the role of iron chelation as adjunctive anti-P. carinii chemotherapy merits additional investigation.In the absence of specific antimicrobial prophylaxis, Pneumocystis carinii causes pneumonia in the majority of individuals infected with human immunodeficiency virus and remains an important pathogen in persons treated with immunosuppressive therapy for malignancy and after organ transplantation (6). The toxicity and the incomplete efficacy of the standard treatment regimens for P. carinii pneumonia have prompted the development of new or adjunctive modes of therapy (6, 27).The availability of iron plays a critical role in host-parasite interactions (13,28,29,41,42). Iron is required for the growth of nearly all forms of bacterial, fungal, protozoal, plant, and animal cells (43,44). Vertebrate animals have developed elaborate strategies to withhold growth-essential iron from microbial invaders while retaining their own access to the metal (41,42,45). It has been suggested, therefore, that manipulation of iron availability be exploited as a therapeutic tool (13,41,42). In fact, several iron chelators, among them deferoxamine (DFO), demonstrate antimalarial activity in cell culture and animal models (14,33,47,48), and recently, iron chelation with DFO has been shown to be an effective adjunct to traditional antimalarial therapy in asymptomatic parasitemic adults and children with cerebral malaria (16,19,40).Clarkson et al. (11) examined the effects of DFO on the progression of reactivated latent P. carinii pneumonia in rats and showed that DFO therapy reduces the lung cyst count in a dose-dependent manner. A subsequent preliminary study from the laboratory of Weinberg and Shaw (46) showed that DFO suppresses the growth of P. carinii in an established cell culture model at concentrations safely achievable in human serum. However, despite the efficacy and safety of DFO as a chelator, i...

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Iron and Infection: The Clinical Evidence

Cited by 41 publications

References 83 publications

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

Iron-deficiency anaemia during the first two years of life

Iron chelators as therapeutic agents against Pneumocystis carinii

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