Serum trace metal and ceruloplasmin variability in individuals treated for pulmonary tuberculosis

Ri, Cernat; Mihăescu, T; Vornicu, M.; Vione, Davide; Olariu, Romeo Iulian; Arsene, Cecilia

doi:10.5588/ijtld.10.0445

Cited by 34 publications

(22 citation statements)

References 25 publications

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“…In addition to weight loss and fungal burden, we monitored serum Cu levels, a biomarker of acute infection. We previously reported a progressive rise in serum Cu levels during the first 72 h of C. albicans infection in BALB/c mice, consistent with other models of infection and inflammation (7,(58)(59)(60)(61)(62)(63). The same increase in serum Cu occurred in C57 mice during C. albicans infection, and there was no difference between WT C57 and CP Ϫ/Ϫ mice (Fig.…”

Section: Resultssupporting

confidence: 61%

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

et al. 2018

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The opportunistic fungal pathogen Candida albicans acquires essential metals from the host, yet the host can sequester these micronutrients through a process known as nutritional immunity. How the host withholds metals from C. albicans has been poorly understood; here we examine the role of calprotectin (CP), a transition metal binding protein. When CP depletes bioavailable Zn from the extracellular environment, C. albicans strongly upregulates ZRT1 and PRA1 for Zn import and maintains constant intracellular Zn through numerous cell divisions. We show for the first time that CP can also sequester Cu by binding Cu(II) with subpicomolar affinity. CP blocks fungal acquisition of Cu from serum and induces a Cu starvation stress response involving SOD1 and SOD3 superoxide dismutases. These transcriptional changes are mirrored when C. albicans invades kidneys in a mouse model of disseminated candidiasis, although the responses to Cu and Zn limitations are temporally distinct. The Cu response progresses throughout 72 h, while the Zn response is short-lived. Notably, these stress responses were attenuated in CP null mice, but only at initial stages of infection. Thus, Zn and Cu pools are dynamic at the hostpathogen interface and CP acts early in infection to restrict metal nutrients from C. albicans.

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Section: Resultssupporting

confidence: 61%

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

et al. 2018

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“…The prenatal treatment was complicated by fetal chorioamnionitis and neonatal sepsis, from which the patient fully recovered. Biochemical responses to infection or inflammation include decreased serum zinc levels and elevated serum ceruloplasmin levels [25], which may have affected some of the values we obtained for these analytes (Table 1 and 2). …”

Section: Discussionmentioning

confidence: 99%

In utero copper treatment for Menkes disease associated with a severe ATP7A mutation

Haddad

Macri

Holmes

et al. 2012

Molecular Genetics and Metabolism

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Menkes disease is a lethal X-linked recessive neurodegenerative disorder of copper transport caused by mutations in ATP7A, which encodes a copper-transporting ATPase. Early postnatal treatment with copper injections often improves clinical outcomes in affected infants. While Menkes disease newborns appear normal neurologically, analyses of fetal tissues including placenta indicate abnormal copper distribution and suggest a prenatal onset of the metal transport defect. In an affected fetus whose parents found termination unacceptable and who understood the associated risks, we began in utero copper histidine treatment at 31.5 weeks gestational age. Copper histidine (900 μg per dose) was administered directly to the fetus by intramuscular injection (fetal quadriceps or gluteus) under ultrasound guidance. Percutaneous umbilical blood sampling enabled serial measurement of fetal copper and ceruloplasmin levels that were used to guide therapy over a four-week period. Fetal copper levels rose from 17 μg/dL prior to treatment to 45 μg/dL, and ceruloplasmin levels from 39 mg/L to 122 mg/L. After pulmonary maturity was confirmed biochemically, the baby was delivered at 35.5 weeks and daily copper histidine therapy (250 μg sc b.i.d.) was begun. Despite this very early intervention with copper, the infant showed hypotonia, developmental delay, and electroencephalographic abnormalities and died of respiratory failure at 5.5 months of age. The patient’s ATP7A mutation, which severely disrupted mRNA splicing, resulted in complete absence of ATP7A protein on Western blots. These investigations suggest that prenatally initiated copper replacement is inadequate to correct Menkes disease caused by severe loss-of-function mutations, and that postnatal ATP7A gene addition represents a rational approach in such circumstances.

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“…Its main physiological role is to oxidize Fe 2+ to Fe 3+ , promoting both Fe mobilization from tissues and loading of ferric iron into serum transferrin [49–51]. Interestingly, ceruloplasmin is also an acute phase protein induced in response to inflammation, trauma, or infection [52], and levels of this protein are induced during infection with bacteria [44], viruses [53] and protozoans [54]. Since one molecule of ceruloplasmin binds 6 atoms of copper, even a modest increase in ceruloplasmin during infection can account for a substantial elevation in serum copper.…”

Section: The Heightened Copper Response Of the Host During Infectionmentioning

confidence: 99%

The Yin and Yang of copper during infection

2016

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Copper is an essential micronutrient for both pathogens and the animal hosts they infect. However, copper can also be toxic in cells due to its redox properties and ability to disrupt active sites of metalloproteins, such as Fe-S enzymes. Through these toxic properties, copper is an effective antimicrobial agent and an emerging concept in innate immunity is that the animal host intentionally exploits copper toxicity in antimicrobial weaponry. In particular, macrophages can attack invading microbes with high copper and this metal is also elevated at sites of lung infection. In addition, copper levels in serum rise during infection with a wide array of pathogens. To defend against this toxic copper, the microbial intruder is equipped with a battery of copper detoxification defenses that promote survival in the host, including copper exporting ATPases and copper binding metallothioneins. However, it is important to remember that copper is also an essential nutrient for microbial pathogens and serves as important cofactor for enzymes such as cytochrome c oxidase for respiration, superoxide dismutase for anti-oxidant defense and multi-copper oxidases that act on metals and organic substrates. We therefore posit that the animal host can also thwart pathogen growth by limiting their copper nutrients, similar to the well-documented nutritional immunity effects for starving microbes of essential zinc, manganese and iron micronutrients. This review provides both sides of the copper story and evaluates how the host can exploit either copper-the-toxin or copper-the-nutrient in antimicrobial tactics at the host-pathogen battleground.

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Serum trace metal and ceruloplasmin variability in individuals treated for pulmonary tuberculosis

Cited by 34 publications

References 25 publications

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

In utero copper treatment for Menkes disease associated with a severe ATP7A mutation

The Yin and Yang of copper during infection

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