Cytosolic tryparedoxin of Leishmania donovani modulates host immune response in visceral leishmaniasis

Suman, Shashi S.; Amit, Ajay; Singh, Krishn Pratap; Gupta, Parool; Equbal, Asif; Kumari, Abha; Topno, Roshan Kamal; Ravidas, Vidyananda; Pandey, Krishna; Bimal, Sanjiva; Das, Pradeep; Ali, Vahab

doi:10.1016/j.cyto.2018.03.010

Cited by 9 publications

(4 citation statements)

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“…The downregulation of RRM1 expression contributes to high concentrations of trypanothione and tryparedoxin. It has been reported that trypanothione and tryparedoxin are involved in diverse cellular functions, including maintenance of thiol redox activity, oxidant defenses, defense against xenobiotics, ascorbate homeostasis, sequestration of heavy metals, drug resistance and modulation of the host immune response ( Fairlamb and Cerami, 1992 ; Schmidt and Krauth-Siegel, 2002 ; Comini et al., 2007 ; Suman et al., 2018 ; Gonzalez-Chavez et al., 2019 ). Moreover, ribonucleotide reductase is responsible for the de novo conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates, providing the precursors necessary for DNA synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…sequestration of heavy metals, drug resistance and modulation of the host immune response (Fairlamb and Cerami, 1992;Schmidt and Krauth-Siegel, 2002;Comini et al, 2007;Suman et al, 2018;Gonzalez-Chavez et al, 2019). Moreover, ribonucleotide reductase is responsible for the de novo conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates, providing the precursors necessary for DNA synthesis.…”

Section: Discussionmentioning

confidence: 99%

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The fungicide pyraclostrobin affects gene expression by altering the DNA methylation pattern in Magnaporthe oryzae

Fang,

Wang,

Qiu

et al. 2024

Front. Plant Sci.

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IntroductionRice blast disease caused by Magnaporthe oryzae has long been the main cause of rice (Oryza sativa L.) yield reduction worldwide. The quinone external inhibitor pyraclostrobin is widely used as a fungicide to effectively control the spread of pathogenic fungi, including M. oryzae. However, M. oryzae can develop resistance through multiple levels of mutation, such as target protein cytb mutation G143A/S, leading to a decrease in the effectiveness of the biocide after a period of application. Therefore, uncovering the possible mutational mechanisms from multiple perspectives will further provide feasible targets for drug development.MethodsIn this work, we determined the gene expression changes in M. oryzae in response to pyraclostrobin stress and their relationship with DNA methylation by transcriptome and methylome.ResultsThe results showed that under pyraclostrobin treatment, endoplasmic reticulum (ER)-associated and ubiquitin-mediated proteolysis were enhanced, suggesting that more aberrant proteins may be generated that need to be cleared. DNA replication and repair processes were inhibited. Glutathione metabolism was enhanced, while lipid metabolism was impaired. The number of alternative splicing events increased. These changes may be related to the elevated methylation levels of cytosine and adenine in gene bodies. Both hypermethylation and hypomethylation of differentially methylated genes (DMGs) mainly occurred in exons and promoters. Some DMGs and differentially expressed genes (DEGs) were annotated to the same pathways by GO and KEGG, including protein processing in the ER, ubiquitin-mediated proteolysis, RNA transport and glutathione metabolism, suggesting that pyraclostrobin may affect gene expression by altering the methylation patterns of cytosine and adenine.DiscussionOur results revealed that 5mC and 6mA in the gene body are associated with gene expression and contribute to adversity adaptation in M. oryzae. This enriched the understanding for potential mechanism of quinone inhibitor resistance, which will facilitate the development of feasible strategies for maintaining the high efficacy of this kind of fungicide.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The fungicide pyraclostrobin affects gene expression by altering the DNA methylation pattern in Magnaporthe oryzae

Fang,

Wang,

Qiu

et al. 2024

Front. Plant Sci.

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“…It has been evidenced that this protein elicits IL-4 and IL-10 expression, and it also suppresses IL-12 and IFN-γ expression in blood-derived monocytes from patients with visceral leishmaniasis. Hence, this protein acts as an immunosuppressant, promoting disease progression ( 50 ). Nevertheless, this protein has not been used as an antigen for vaccine development against leishmaniasis.…”

Section: Discussionmentioning

confidence: 99%

Identification of Immunodominant Antigens From a First-Generation Vaccine Against Cutaneous Leishmaniasis

et al. 2022

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Leishmaniasis is a neglected tropical disease (NTD) caused by parasites belonging to the Leishmania genus for which there is no vaccine available for human use. Thus, the aims of this study are to evaluate the immunoprotective effect of a first-generation vaccine against L. amazonensis and to identify its immunodominant antigens. BALB/c mice were inoculated with phosphate buffer sodium (PBS), total L. amazonensis antigens (TLAs), or TLA with Poly (I:C) and Montanide ISA 763. The humoral and cellular immune response was evaluated before infection. IgG, IgG1, and IgG2a were measured on serum, and IFN-γ, IL-4, and IL-10 cytokines as well as cell proliferation were measured on a splenocyte culture from vaccinated mice. Immunized mice were challenged with 104 infective parasites of L. amazonensis on the footpad. After infection, the protection provided by the vaccine was analyzed by measuring lesion size, splenic index, and parasite load on the footpad and spleen. To identify immunodominant antigens, total proteins of L. amazonensis were separated on 2D electrophoresis gel and transferred to a membrane that was incubated with serum from immunoprotected mice. The antigens recognized by the serum were analyzed through a mass spectrometric assay (LC-MS/MS-IT-TOF) to identify their protein sequence, which was subjected to bioinformatic analysis. The first-generation vaccine induced higher levels of antibodies, cytokines, and cell proliferation than the controls after the second dose. Mice vaccinated with TLA + Poly (I:C) + Montanide ISA 763 showed less footpad swelling, a lower splenic index, and a lower parasite load than the control groups (PBS and TLA). Four immunodominant proteins were identified by mass spectrometry: cytosolic tryparedoxin peroxidase, an uncharacterized protein, a kinetoplast-associated protein-like protein, and a putative heat-shock protein DNAJ. The identified proteins showed high levels of conserved sequence among species belonging to the Leishmania genus and the Trypanosomatidae family. These proteins also proved to be phylogenetically divergent to human and canine proteins. TLA + Poly (I:C) + Montanide ISA 763 could be used as a first-generation vaccine against leishmaniasis. The four proteins identified from the whole-protein vaccine could be good antigen candidates to develop a new-generation vaccine against leishmaniasis.

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“…Studies have revealed that trypanothione reductase, the enzyme that maintain trypanothione in its reduced form, is important for the parasite to stay alive against the oxidative stress inside the macrophages ( 13 ). Knock-out mutants by gene disruption in L.donovani and L.major strains by means of the selectable markers neomycin and hygromycin phosphotransferases show weakened infectivity and a reduced survival capacity in the macrophages ( 14 ). Tunes, Morato ( 15 ) revealed that using gold complexes can act against L. infantum and L. braziliensis intracellular amastigotes by causing mitochondrial damage and oxidative stress due to creation of reactive oxygen species.…”

Section: Introductionmentioning

confidence: 99%

Major Molecular Factors Related to Leishmania Pathogenicity

Al-Khalaifah

2022

Front. Immunol.

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Leishmaniasis is a major health problem with 600k - 1M new cases worldwide and 1 billion at risk. It involves a wide range of clinical forms ranging from self-healing cutaneous lesions to systemic diseases that are fatal if not treated, depending on the species of Leishmania. Leishmania sp. are digenetic parasites that have two different morphological stages. Leishmania parasites possess a number of invasive/evasive and pathoantigenic determinants that seem to have critical roles in Leishmania infection of macrophages which leads to successful intracellular parasitism in the parasitophorous vacuoles. These determinants are traditionally known as “virulence factors”, and are considered to be good targets for developing specific inhibitors to attenuate virulence of Leishmania by gene deletions or modifications, thus causing infective, but non-pathogenic mutants for vaccination. Pathway of biosynthesis is critical for keeping the parasite viable and is important for drug designing against these parasites. These drugs are aimed to target enzymes that control these pathways. Accordingly, maintaining low level of parasitic infection and in some cases as a weapon to eradicate infection completely. The current paper focuses on several virulence factors as determinants of Leishmania pathogenicity, as well as the metabolites produced by Leishmania to secure its survival in the host.

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Cytosolic tryparedoxin of Leishmania donovani modulates host immune response in visceral leishmaniasis

Cited by 9 publications

References 58 publications

The fungicide pyraclostrobin affects gene expression by altering the DNA methylation pattern in Magnaporthe oryzae

The fungicide pyraclostrobin affects gene expression by altering the DNA methylation pattern in Magnaporthe oryzae

Identification of Immunodominant Antigens From a First-Generation Vaccine Against Cutaneous Leishmaniasis

Major Molecular Factors Related to Leishmania Pathogenicity

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