Iron-withholding strategy in innate immunity

Ong, Sek Tong; Ho, Jason Zhe Shan; Ho, Bow; Ding, Jeak Ling

doi:10.1016/j.imbio.2006.02.004

Cited by 235 publications

(189 citation statements)

References 171 publications

(184 reference statements)

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“…The solid was washed several times with diethyl ether and then dissolved in water (50 ml) and washed with diethyl ether (2 ϫ 25 ml). The water was removed using high vacuum rotary evaporation (1 mm Hg), which gave 6 as a hydroscopic white foam (363 mg, 93%): 1 (7)-The dihydrobromide salt 6 (150 mg, 0.484 mmol) was dissolved in water (1.0 ml), and the solution was adjusted to pH 4.5 with pyridine. The water was removed using high vacuum rotary evaporation (1 mm Hg), which gave a clear oil.…”

Section: Methodsmentioning

confidence: 99%

“…Pathogenic microbes have evolved a range of strategies for co-opting, transporting, and storing the iron they scavenge from their hosts (1,2). Central to iron trafficking in many microbes are siderophores, small molecular weight secondary metabolites that competitively chelate and repackage host iron for uptake and/or intracellular storage by the pathogen (3,4).…”

mentioning

confidence: 99%

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Comprehensive Spectroscopic, Steady State, and Transient Kinetic Studies of a Representative Siderophore-associated Flavin Monooxygenase

Mayfield

Frederick

Streit

et al. 2010

Journal of Biological Chemistry

113

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Comprehensive Spectroscopic, Steady State, and Transient Kinetic Studies of a Representative Siderophore-associated Flavin Monooxygenase

Mayfield

Frederick

Streit

et al. 2010

Journal of Biological Chemistry

113

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“…The resulting ferric iron could be loaded onto transferrin and transported to iron-deficient cells for uptake, as is the case in mammals (31). Alternatively, oxidation of ferrous iron followed by transferrin loading may play a protective role by limiting toxic radical formation, which is generated by ferrous but not ferric iron (1), or, it may have an immune function, given that ferric-transferrin is less likely than free iron to serve as a source of iron for pathogens (32). The possibility of an immune function is supported by up-regulation of MCO1 in D. melanogaster (33) and A. gambiae (19) in response to infection.…”

Section: Mco1 Is Present On Basal Surface Of Digestive System and Malmentioning

confidence: 99%

Multicopper oxidase-1 is a ferroxidase essential for iron homeostasis in Drosophila melanogaster

Lang

Braun

Kanost

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Multicopper ferroxidases catalyze the oxidation of ferrous iron to ferric iron. In yeast and algae, they participate in cellular uptake of iron; in mammals, they facilitate cellular efflux. The mechanisms of iron metabolism in insects are still poorly understood, and insect multicopper ferroxidases have not been identified. In this paper, we present evidence that Drosophila melanogaster multicopper oxidase-1 (MCO1) is a functional ferroxidase. We identified candidate iron-binding residues in the MCO1 sequence and found that purified recombinant MCO1 oxidizes ferrous iron. An association between MCO1 function and iron homeostasis was confirmed by two observations: RNAi-mediated knockdown of MCO1 resulted in decreased iron accumulation in midguts and whole insects, and weak knockdown increased the longevity of flies fed a toxic concentration of iron. Strong knockdown of MCO1 resulted in pupal lethality, indicating that MCO1 is an essential gene. Immunohistochemistry experiments demonstrated that MCO1 is located on the basal surfaces of the digestive system and Malpighian tubules. We propose that MCO1 oxidizes ferrous iron in the hemolymph and that the resulting ferric iron is bound by transferrin or melanotransferrin, leading to iron storage, iron withholding from pathogens, regulation of oxidative stress, and/or epithelial maturation. These proposed functions are distinct from those of other known ferroxidases. Given that MCO1 orthologues are present in all insect genomes analyzed to date, this discovery is an important step toward understanding iron metabolism in insects.

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“…Access to iron within the host is a prerequisite for the successful establishment of infection, and iron limitation is a wellcharacterized element of innate immunity (24,34). Host systemic iron availability is restricted by the iron chelator transferrin, whose tight affinity for ferric iron is sufficient to inhibit the growth of the pathogen Bacillus anthracis, the causative agent of the mammalian disease anthrax, in human serum (32).…”

mentioning

confidence: 99%

Cellular Iron Distribution in Bacillus anthracis

Pohl

Gray

et al. 2011

Journal of Bacteriology

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Although successful iron acquisition by pathogens within a host is a prerequisite for the establishment of infection, surprisingly little is known about the intracellular distribution of iron within bacterial pathogens. We have used a combination of anaerobic native liquid chromatography, inductively coupled plasma mass spectrometry, principal-component analysis, and peptide mass fingerprinting to investigate the cytosolic iron distribution in the pathogen Bacillus anthracis. Our studies identified three of the major iron pools as being associated with the electron transfer protein ferredoxin, the miniferritin Dps2, and the superoxide dismutase (SOD) enzymes SodA1 and SodA2. Although both SOD isozymes were predicted to utilize manganese cofactors, quantification of the metal ions associated with SodA1 and SodA2 in cell extracts established that SodA1 is associated with both manganese and iron, whereas SodA2 is bound exclusively to iron in vivo. These data were confirmed by in vitro assays using recombinant protein preparations, showing that SodA2 is active with an iron cofactor, while SodA1 is cambialistic, i.e., active with manganese or iron. Furthermore, we observe that B. anthracis cells exposed to superoxide stress increase their total iron content more than 2-fold over 60 min, while the manganese and zinc contents are unaffected. Notably, the acquired iron is not localized to the three identified cytosolic iron pools.

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Iron-withholding strategy in innate immunity

Cited by 235 publications

References 171 publications

Comprehensive Spectroscopic, Steady State, and Transient Kinetic Studies of a Representative Siderophore-associated Flavin Monooxygenase

Comprehensive Spectroscopic, Steady State, and Transient Kinetic Studies of a Representative Siderophore-associated Flavin Monooxygenase

Multicopper oxidase-1 is a ferroxidase essential for iron homeostasis in Drosophila melanogaster

Cellular Iron Distribution in Bacillus anthracis

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