Zinc/copper imbalance reflects immune dysfunction in human leishmaniasis: an ex vivo and in vitro study

Weyenbergh, Johan Van; Santana, Guilherme; Júnior, Argemiro D’Oliveira; Santos, Anibal Ferreira dos; Costa, Carlos Henrique Nery; Carvalho, Edgar M.; Barral, Aldina; Barral‐Netto, Manoel

doi:10.1186/1471-2334-4-50

Cited by 57 publications

(47 citation statements)

References 21 publications

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“…One of these is acute cutaneous leishmaniasis, induced by different forms of Leishmania. Patients with cutaneous, mucosal, and visceral leishmaniasis display lower plasma zinc levels [161]. As a result of zinc therapy, a dose--dependent decrease in erythemas and size of induration and an increased cure rate were found [147].…”

Section: Parasitic Infectionsmentioning

confidence: 99%

Modulating the immune response by oral zinc supplementation: a single approach for multiple diseases

Overbeck

Rink

Haase

2008

Arch. Immunol. Ther. Exp.

172

116

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Zinc is required for multiple cellular tasks, and especially the immune system depends on a sufficient availability of this essential trace element. During the last decades, many studies attempted to affect the outcome of various diseases by zinc supplementation. These efforts either aimed at supporting immunity by zinc administration or at correcting a loss of zinc secondary to the disease to restore the zinc-dependent functions of the immune system. This review aims to summarize the respective findings and to discuss possible molecular mechanisms by which zinc could influence viral, bacterial, and parasitic infections, autoimmune diseases, and the response to vaccination. Zinc supplementation in diseases such as diarrhea, chronic hepatitis C, shigellosis, leprosy, tuberculosis, pneumonia, acute lower respiratory infection, and leishmaniasis seems beneficial. In contrast, the results for the common cold and malaria are still not conclusive, and zinc was ineffective in most vaccination and rheumatoid arthritis studies. For AIDS and type 1 diabetes, zinc supplementation may even be a risk factor for increased mortality or deterioration of the glucose metabolism, respectively. In these cases, zinc supplementation should be used with care and limited to clearly zinc-deficient individuals.

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Section: Parasitic Infectionsmentioning

confidence: 99%

Modulating the immune response by oral zinc supplementation: a single approach for multiple diseases

Overbeck

Rink

Haase

2008

Arch. Immunol. Ther. Exp.

172

116

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“…Van Heugten et al (2003) reported that pigs supplemented with Zn had greater lymphocyte proliferation than pigs fed the control diet. Meanwhile, Weyenbergh et al (2004) reported that increased Cu levels inhibited in vitro IFN-γ production. Pocino et al (1991) showed decreased lymphocyte proliferation in response to concanavalin A in mice fed excess Cu, but it was increased in response to E. coli lipopolysaccharide stimulation, whereas Davis et al (2002) indicated no response of lymphocytes of pigs fed pharmacological levels of dietary Cu.…”

Section: Immune Responsementioning

confidence: 99%

“…Deficiencies of Zn and Cu reduce immune function and increase susceptibility to disease (Neldner and Hambidge 1975;James 1990;Stabel and Spears 1990). Bao et al (2003) reported that Zn supplementation might reduce the gene expression for cytotoxic cytokines that increase amounts of free radicals, whereas Weyenbergh et al (2004) increased Cu levels inhibited in vitro interferon-γ (IFN-γ) production. Although the immune function is well established, the impact of feeding pharmacological levels of dietary Zn and Cu in the short and medium terms are not well established in young piglets.…”

mentioning

confidence: 99%

Effect of pharmacological intakes of zinc and copper on growth performance, circulating cytokines and gut microbiota of newly weaned piglets challenged with coliform lipopolysaccharides

Namkung¹,

Gong²,

Yu³

et al. 2006

Can. J. Anim. Sci.

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. 2006. Effect of pharmacological intakes of zinc and copper on growth performance, circulating cytokines and gut microbiota of newly weaned piglets challenged with coliform lipopolysaccharides. Can. J. Anim. Sci. 86: 511-522. The effect of feeding pharmacological levels of zinc (Zn) and copper (Cu) to newly weaned piglets on growth performance, circulating cytokines levels and gut microbiota was investigated. One hundred eighty piglets [5.90 ± 0.18 kg body weight (BW); six pigs per pen] weaned at 16 to 19 d of age were fed diets containing 3000 ppm additional Zn, 250 ppm additional Cu or a control diet (150 ppm Zn, 15 ppm Cu) for 14 d post-weaning (weeks 1 and 2). Pigs were fed a control diet for an additional 2 wk. Pigs were injected intramuscularly on days 13 and 19 with either 75 µg kg -1 BW of coliform lipopolysaccharide (LPS) or an equivalent amount of saline. Blood samples were collected 3 h after LPS injection to measure plasma levels of cytokines and cortisol. Digesta of ileum and colon were collected from non-challenged pigs on days 14 and 28 to evaluate microbiota using conventional culturing methods and polymerase chain reaction and denaturing gradient gel electrophoresis (PCR-DGGE) analysis of the 16S rRNA genes. There were no interactive effects of diet and LPS challenge on growth performance (P > 0.10). Compared with the control, high dietary Zn and Cu increased (P < 0.01) average daily gain (ADG) during weeks 1 (0.125, 0.091 vs. 0.074 kg; P < 0.05) and 2 (0.240, 0.270 vs. 0.155 kg; P < 0.01) only. LPS injection reduced ADG during weeks 2 and 4 (P < 0.01). Dietary treatment did not affect feed efficiency (P > 0.10). Challenging pigs with LPS reduced (P < 0.01) feed efficiency during week 2, but increased (P < 0.05) feed efficiency during week 3. There were no interactive effects between diet and LPS on plasma cytokines levels, except for cortisol (P < 0.05). Plasma levels of cytokines (interleukin-1β, interferon-γ, tumour necrosis factor-α) and cortisol increased (P < 0.01) in pigs challenged with LPS. The high levels of dietary Zn and Cu reduced (P < 0.05) the increases in plasma cortisol level in LPS-challenged pigs at days 9 and 19. There were no differences among the dietary treatments in counts of coliforms and lactobacillus in the digesta from ileum and colon (P > 0.10). PCR-DGGE analysis showed that high levels of dietary Zn and particularly Cu significantly reduced the diversity of ileal microbiota. The effect on microbiota diversity was reversible when dietary Zn and Cu were removed. Enhanced growth performance of the newly weaned piglets fed high dietary Zn and Cu appears mediated via changes in gut microbiota as well as a reduced cortisol response following an immune challenge.

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“…On the other hand, zinc is an essential trace element for humans and its deficiency leads to decreased recruitment of naive T cells and reduced expression of Th1 cytokines (IFN-␥, interleukin-2, and tumor necrosis factor alpha) (26). This immune impairment could explain in part observations made in patients with mucocutaneous and visceral leishmaniasis in whom significantly lower plasma levels of zinc were found compared to normal endemic controls (27). Therefore, supplementing zinc in a deficient host could favor the development of a protective Th1-mediated response against Leishmania.…”

mentioning

confidence: 80%

Antileishmanial Activity of Disulfiram and Thiuram Disulfide Analogs in anEx VivoModel System Is Selectively Enhanced by the Addition of Divalent Metal Ions

Peniche

Renslo

Melby

et al. 2015

Antimicrob Agents Chemother

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dCurrent treatments for cutaneous and visceral leishmaniasis are toxic, expensive, difficult to administer, and limited in efficacy and availability. Disulfiram has primarily been used to treat alcoholism. More recently, it has shown some efficacy as therapy against protozoan pathogens and certain cancers, suggesting a wide range of biological activities. We used an ex vivo system to screen several thiuram disulfide compounds for antileishmanial activity. We found five compounds (compound identifier [CID] 7188, 5455, 95876, 12892, and 3117 [disulfiram]) with anti-Leishmania activity at nanomolar concentrations. We further evaluated these compounds with the addition of divalent metal salts based on studies that indicated these salts could potentiate the action of disulfiram. In addition, clinical studies suggested that zinc has some efficacy in treating cutaneous leishmaniasis. Several divalent metal salts were evaluated at 1 M, which is lower than the normal levels of copper and zinc in plasma of healthy individuals. The leishmanicidal activity of disulfiram and CID 7188 were enhanced by several divalent metal salts at 1 M. The in vitro therapeutic index (IVTI) of disulfiram and CID 7188 increased 12-and 2.3-fold, respectively, against L. major when combined with ZnCl 2 . The combination of disulfiram with ZnSO 4 resulted in a 1.8-fold increase in IVTI against L. donovani. This novel combination of thiuram disulfides and divalent metal ions salts could have application as topical and/or oral therapies for treatment of cutaneous and visceral leishmaniasis.T he leishmaniases are vector-borne parasitic diseases with a significant global impact. These diseases occur in more than 88 countries of the world, where approximately 350 million people are at risk. In the Old World, visceral and cutaneous leishmaniasis are caused by the intracellular protozoa Leishmania donovani and Leishmania major, respectively. Visceral leishmaniasis is characterized by impaired parasite-specific cell-mediated immunity and progressive hepatosplenomegaly, anemia, and weight loss and is frequently fatal if left untreated (1). In cutaneous leishmaniasis (CL), the disease severity varies considerably from single self-resolving skin nodules or ulcers to one or more nonhealing lesions, which can be disfiguring (2). The healing response is generally associated with expansion of parasite-specific gamma interferon (IFN-␥)-producing T cells (3).All currently available drug therapies for leishmaniasis have potentially harmful side effects and documented limitations in efficacy. The pentavalent antimony compounds, which are still widely used in many countries, are suboptimal because of the difficulty of administration, well-known host toxicity, and increasing parasite drug resistance. Cure rates have been noted recently to be unacceptably low (4). Other therapies, including amphotericin B desoxycholate and its liposomal formulation, and miltefosine, have been increasingly used in the treatment of visceral or cutaneous leishmaniasis. Their use is al...

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Zinc/copper imbalance reflects immune dysfunction in human leishmaniasis: an ex vivo and in vitro study

Cited by 57 publications

References 21 publications

Modulating the immune response by oral zinc supplementation: a single approach for multiple diseases

Modulating the immune response by oral zinc supplementation: a single approach for multiple diseases

Effect of pharmacological intakes of zinc and copper on growth performance, circulating cytokines and gut microbiota of newly weaned piglets challenged with coliform lipopolysaccharides

Antileishmanial Activity of Disulfiram and Thiuram Disulfide Analogs in anEx VivoModel System Is Selectively Enhanced by the Addition of Divalent Metal Ions

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