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Genomic and Transcriptomic Analysis for Identification of Genes and Interlinked Pathways Mediating Artemisinin Resistance in Leishmania donovani

Current therapy for visceral leishmaniasis (VL), compromised by drug resistance, toxicity, and high cost, demands for more effective, safer, and low-cost drugs. Artemisinin has been found to be an effectual drug alternative in experimental models of leishmaniasis. Comparative genome and transcriptom...

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Autores principales: Ghosh, Sushmita, Verma, Aditya, Kumar, Vinay, Pradhan, Dibyabhaba, Selvapandiyan, Angamuthu, Salotra, Poonam, Singh, Ruchi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698566/
https://www.ncbi.nlm.nih.gov/pubmed/33213096
http://dx.doi.org/10.3390/genes11111362
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author Ghosh, Sushmita
Verma, Aditya
Kumar, Vinay
Pradhan, Dibyabhaba
Selvapandiyan, Angamuthu
Salotra, Poonam
Singh, Ruchi
author_facet Ghosh, Sushmita
Verma, Aditya
Kumar, Vinay
Pradhan, Dibyabhaba
Selvapandiyan, Angamuthu
Salotra, Poonam
Singh, Ruchi
author_sort Ghosh, Sushmita
collection PubMed
description Current therapy for visceral leishmaniasis (VL), compromised by drug resistance, toxicity, and high cost, demands for more effective, safer, and low-cost drugs. Artemisinin has been found to be an effectual drug alternative in experimental models of leishmaniasis. Comparative genome and transcriptome analysis of in vitro-adapted artesunate-resistant (K133AS-R) and -sensitive wild-type (K133WT) Leishmania donovani parasites was carried out using next-generation sequencing and single-color DNA microarray technology, respectively, to identify genes and interlinked pathways contributing to drug resistance. Whole-genome sequence analysis of K133WT vs. K133AS-R parasites revealed substantial variation among the two and identified 240 single nucleotide polymorphisms (SNPs), 237 insertion deletions (InDels), 616 copy number variations (CNVs) (377 deletions and 239 duplications), and trisomy of chromosome 12 in K133AS-R parasites. Transcriptome analysis revealed differential expression of 208 genes (fold change ≥ 2) in K133AS-R parasites. Functional categorization and analysis of modulated genes of interlinked pathways pointed out plausible adaptations in K133AS-R parasites, such as (i) a dependency on lipid and amino acid metabolism for generating energy, (ii) reduced DNA and protein synthesis leading to parasites in the quiescence state, and (iii) active drug efflux. The upregulated expression of cathepsin-L like protease, amastin-like surface protein, and amino acid transporter and downregulated expression of the gene encoding ABCG2, pteridine receptor, adenylatecyclase-type receptor, phosphoaceylglucosamine mutase, and certain hypothetical proteins are concordant with genomic alterations suggesting their potential role in drug resistance. The study provided an understanding of the molecular basis linked to artemisinin resistance in Leishmania parasites, which may be advantageous for safeguarding this drug for future use.
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spelling pubmed-76985662020-11-29 Genomic and Transcriptomic Analysis for Identification of Genes and Interlinked Pathways Mediating Artemisinin Resistance in Leishmania donovani Ghosh, Sushmita Verma, Aditya Kumar, Vinay Pradhan, Dibyabhaba Selvapandiyan, Angamuthu Salotra, Poonam Singh, Ruchi Genes (Basel) Article Current therapy for visceral leishmaniasis (VL), compromised by drug resistance, toxicity, and high cost, demands for more effective, safer, and low-cost drugs. Artemisinin has been found to be an effectual drug alternative in experimental models of leishmaniasis. Comparative genome and transcriptome analysis of in vitro-adapted artesunate-resistant (K133AS-R) and -sensitive wild-type (K133WT) Leishmania donovani parasites was carried out using next-generation sequencing and single-color DNA microarray technology, respectively, to identify genes and interlinked pathways contributing to drug resistance. Whole-genome sequence analysis of K133WT vs. K133AS-R parasites revealed substantial variation among the two and identified 240 single nucleotide polymorphisms (SNPs), 237 insertion deletions (InDels), 616 copy number variations (CNVs) (377 deletions and 239 duplications), and trisomy of chromosome 12 in K133AS-R parasites. Transcriptome analysis revealed differential expression of 208 genes (fold change ≥ 2) in K133AS-R parasites. Functional categorization and analysis of modulated genes of interlinked pathways pointed out plausible adaptations in K133AS-R parasites, such as (i) a dependency on lipid and amino acid metabolism for generating energy, (ii) reduced DNA and protein synthesis leading to parasites in the quiescence state, and (iii) active drug efflux. The upregulated expression of cathepsin-L like protease, amastin-like surface protein, and amino acid transporter and downregulated expression of the gene encoding ABCG2, pteridine receptor, adenylatecyclase-type receptor, phosphoaceylglucosamine mutase, and certain hypothetical proteins are concordant with genomic alterations suggesting their potential role in drug resistance. The study provided an understanding of the molecular basis linked to artemisinin resistance in Leishmania parasites, which may be advantageous for safeguarding this drug for future use. MDPI 2020-11-17 /pmc/articles/PMC7698566/ /pubmed/33213096 http://dx.doi.org/10.3390/genes11111362 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ghosh, Sushmita
Verma, Aditya
Kumar, Vinay
Pradhan, Dibyabhaba
Selvapandiyan, Angamuthu
Salotra, Poonam
Singh, Ruchi
Genomic and Transcriptomic Analysis for Identification of Genes and Interlinked Pathways Mediating Artemisinin Resistance in Leishmania donovani
title Genomic and Transcriptomic Analysis for Identification of Genes and Interlinked Pathways Mediating Artemisinin Resistance in Leishmania donovani
title_full Genomic and Transcriptomic Analysis for Identification of Genes and Interlinked Pathways Mediating Artemisinin Resistance in Leishmania donovani
title_fullStr Genomic and Transcriptomic Analysis for Identification of Genes and Interlinked Pathways Mediating Artemisinin Resistance in Leishmania donovani
title_full_unstemmed Genomic and Transcriptomic Analysis for Identification of Genes and Interlinked Pathways Mediating Artemisinin Resistance in Leishmania donovani
title_short Genomic and Transcriptomic Analysis for Identification of Genes and Interlinked Pathways Mediating Artemisinin Resistance in Leishmania donovani
title_sort genomic and transcriptomic analysis for identification of genes and interlinked pathways mediating artemisinin resistance in leishmania donovani
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698566/
https://www.ncbi.nlm.nih.gov/pubmed/33213096
http://dx.doi.org/10.3390/genes11111362
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