Functional analysis of iron superoxide dismutase-A in wild-type and antimony-resistant Leishmania braziliensis and Leishmania infantum lines

Tessarollo, Nayara G.; Andrade, Juvana Moreira; Moreira, Douglas S.; Murta, Silvane Maria Fonseca

doi:10.1016/j.parint.2014.11.001

Cited by 28 publications

(23 citation statements)

References 24 publications

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“…It was demonstrated that SbIII or MIL resistant parasites present significantly lower levels of ROS compared to wild-type cells [13] and this suggests that SbIII and MIL resistant Leishmania are probably able to maintain mitochondrial ROS to a level similar or lower than wild-type, either by more effective scavenging or by decreased ROS production. An increase in the level of several antioxidant molecules has already been reported to help dealing with ROS induced upon drug treatment, including an increase in the levels of glutathione/trypanothione [37,38] and an increase in the activity of the superoxide dismutase A (SODA) [25,39]. Our proteomic work led to the identification of additional factors that may help to control the ROS levels in resistant parasites.…”

Section: Discussionmentioning

confidence: 84%

Mitochondrial Proteomics of Antimony and Miltefosine Resistant Leishmania infantum

et al. 2015

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Antimony (SbIII) and miltefosine (MIL) are important drugs for the treatment of Leishmania parasite infections. The mitochondrion is likely to play a central role in SbIII and MIL induced cell death in this parasite. Enriched mitochondrial samples from Leishmania promastigotes selected step by step for in vitro resistance to SbIII and MIL were subjected to differential proteomic analysis. A shared decrease in both mutants in the levels of pyruvate dehydrogenase, dihydrolipoamide dehydrogenase, and isocitrate dehydrogenase was observed, as well as a differential abundance in two calcium-binding proteins and the unique dynamin-1-like protein of the parasite. Both mutants presented a shared increase in the succinyl-CoA:3-ketoacid-coenzyme A transferase and the abundance of numerous hypothetical proteins was also altered in both mutants. In general, the proteomic changes observed in the MIL mutant were less pronounced than in the SbIII mutant, probably due to the early appearance of a mutation in the miltefosine transporter abrogating the need for a strong mitochondrial adaptation. This study is the first analysis of the Leishmania mitochondrial proteome and offers powerful insights into the adaptations to this organelle during SbIII and MIL drug resistance.

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Section: Discussionmentioning

confidence: 84%

Mitochondrial Proteomics of Antimony and Miltefosine Resistant Leishmania infantum

et al. 2015

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“…While effective, patients treated with this drug present local and systemic side effects, such as nausea, vomiting, weakness, myalgia, abdominal pain, skin rash, liver and heart toxicities (McGwire and Satoskar, 2014). Moreover, some reports suggest that in the New World L. ( Viannia ) braziliensis , L. (V.) guyanensis and L. (L.) infantum have acquired increased resistance against antimonial drugs (Tessarollo et al., 2015, de Moura et al., 2016, Moreira et al., 2015, Monte-Neto et al., 2015). …”

Section: Introductionmentioning

confidence: 99%

Therapeutic effect of ursolic acid in experimental visceral leishmaniasis

Jesus

Fragoso

Yamamoto

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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Leishmaniasis is an important neglected tropical disease, affecting more than 12 million people worldwide. The available treatments are not well tolerated and present diverse side effects in patients, justifying the search for new therapeutic compounds. In the present study, the therapeutic potential and toxicity of ursolic acid (UA), isolated from the leaves of Baccharis uncinella C. DC. (Asteraceae), were evaluated in experimental visceral leishmaniasis. To evaluate the therapeutic potential of UA, hamsters infected with L. (L.) infantum were treated daily during 15 days with 1.0 or 2.0 mg UA/kg body weight, or with 5.0 mg amphotericin B/kg body weight by intraperitoneal route. Fifteen days after the last dose, the parasitism of the spleen and liver was stimated and the main histopathological alterations were recorded. The proliferation of splenic mononuclear cells was evaluated and IFN-γ, IL-4, and IL-10 gene expressions were analyzed in spleen fragments. The toxicity of UA and amphotericin B were evaluated in healthy golden hamsters by histological analysis and biochemical parameters. Animals treated with UA had less parasites in the spleen and liver when compared with the infected control group, and they also showed preservation of white and red pulps, which correlate with a high rate of proliferation of splenic mononuclear cells, IFN-γ mRNA and iNOS production. Moreover, animals treated with UA did not present alterations in the levels of AST, ALT, creatinine and urea. Taken together, these findings indicate that UA is an interesting natural compound that should be considered for the development of prototype drugs against visceral leishmaniasis.

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“…They are organized in three families based on the metal ion that supports activity: Ni, Cu complexed with Zn, and Mn or Fe [ 42 ]. Eukaryotes including mammals have Cu/ Mn/ ZnSODs, whereas FeSODs have been found in prokaryotes, protozoans, plants, and algae [ 43 ]. Different FeSOD species (FeSOD-A and FeSOD-B) have been characterized in L .…”

Section: Discussionmentioning

confidence: 99%

Quantitative proteomic analysis of amastigotes from Leishmania (L.) amazonensis LV79 and PH8 strains reveals molecular traits associated with the virulence phenotype

et al. 2017

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BackgroundLeishmaniasis is an antropozoonosis caused by Leishmania parasites that affects around 12 million people in 98 different countries. The disease has different clinical forms, which depend mainly on the parasite genetics and on the immunologic status of the host. The promastigote form of the parasite is transmitted by an infected female phlebotomine sand fly, is internalized by phagocytic cells, mainly macrophages, and converts into amastigotes which replicate inside these cells. Macrophages are important cells of the immune system, capable of efficiently killing intracellular pathogens. However, Leishmania can evade these mechanisms due to expression of virulence factors. Different strains of the same Leishmania species may have different infectivity and metastatic phenotypes in vivo, and we have previously shown that analysis of amastigote proteome can give important information on parasite infectivity. Differential abundance of virulence factors probably accounts for the higher virulence of PH8 strain parasites shown in this work. In order to test this hypothesis, we have quantitatively compared the proteomes of PH8 and LV79 lesion-derived amastigotes using a label-free proteomic approach.Methodology/Principal findingsIn the present work, we have compared lesion development by L. (L.) amazonensis PH8 and LV79 strains in mice, showing that they have different virulence in vivo. Viability and numbers of lesion-derived amastigotes were accordingly significantly different. Proteome profiles can discriminate parasites from the two strains and several proteins were differentially expressed.Conclusions/SignificanceThis work shows that PH8 strain is more virulent in mice, and that lesion-derived parasites from this strain are more viable and more infective in vitro. Amastigote proteome comparison identified GP63 as highly expressed in PH8 strain, and Superoxide Dismutase, Tryparedoxin Peroxidase and Heat Shock Protein 70 as more abundant in LV79 strain. The expression profile of all proteins and of the differential ones precisely classified PH8 and LV79 samples, indicating that the two strains have proteins with different abundances and that proteome profiles correlate with their phenotypes.

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Functional analysis of iron superoxide dismutase-A in wild-type and antimony-resistant Leishmania braziliensis and Leishmania infantum lines

Cited by 28 publications

References 24 publications

Mitochondrial Proteomics of Antimony and Miltefosine Resistant Leishmania infantum

Mitochondrial Proteomics of Antimony and Miltefosine Resistant Leishmania infantum

Therapeutic effect of ursolic acid in experimental visceral leishmaniasis

Quantitative proteomic analysis of amastigotes from Leishmania (L.) amazonensis LV79 and PH8 strains reveals molecular traits associated with the virulence phenotype

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