Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance
Abstract Background Leishmaniasis is a neglected tropical disease affecting millions of people worldwide. Emerging drug resistance of Leishmania species poses threaten to the effective control and elimination programme of this neglected tropical disease. Methods In this work, we conducted drug-resis...
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| Format: | Article |
| Language: | English |
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BMC
2020-10-01
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| Series: | Parasites & Vectors |
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| Online Access: | http://link.springer.com/article/10.1186/s13071-020-04397-4 |
| _version_ | 1819315585657339904 |
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| author | Zhiwan Zheng Jianping Chen Guangxu Ma Abhay R. Satoskar Jiao Li |
| author_facet | Zhiwan Zheng Jianping Chen Guangxu Ma Abhay R. Satoskar Jiao Li |
| author_sort | Zhiwan Zheng |
| collection | DOAJ |
| description | Abstract Background Leishmaniasis is a neglected tropical disease affecting millions of people worldwide. Emerging drug resistance of Leishmania species poses threaten to the effective control and elimination programme of this neglected tropical disease. Methods In this work, we conducted drug-resistance testing, whole genome resequencing and proteome profiling for a recently reported clinical isolate with supposed drug resistance (HCZ), and two reference sensitive strains (DD8 and 9044) of Leishmania donovani, to explore molecular mechanisms underlying drug resistance in this parasite. Results With reference to DD8 and 9044 strains, HCZ isolate showed higher-level virulence and clear resistance to antimonials in promastigote culture, infected macrophages and animal experiment. Pairwise genomic comparisons revealed genetic variations (86 copy number variations, 271 frameshift mutations in protein-coding genes and two site mutations in non-coding genes) in HCZ isolate that were absent from the reference sensitive strains. Proteomic analysis indicated different protein expression between HCZ isolate and reference strains, including 69 exclusively detected proteins and 82 consistently down-/upregulated molecules in the HCZ isolate. Integrative analysis showed linkage of 12 genomic variations (gene duplication, insertion and deletion) and their protein expression changes in HCZ isolate, which might be associated with pathogenic and antimony-resistant phenotype. Functional annotation analyses further indicated that molecules involved in nucleotide-binding, fatty acid metabolism, oxidation-reduction and transport might play a role in host-parasite interaction and drug-resistance. Conclusions This comprehensive integrative work provided novel insights into the genetic basis underlying virulence and resistance, suggesting new aspects to be investigated for a better intervention against L. donovani and associated diseases. |
| first_indexed | 2024-12-24T10:02:27Z |
| format | Article |
| id | doaj.art-a184315146584fe396d9614a12a30212 |
| institution | Directory Open Access Journal |
| issn | 1756-3305 |
| language | English |
| last_indexed | 2024-12-24T10:02:27Z |
| publishDate | 2020-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Parasites & Vectors |
| spelling | doaj.art-a184315146584fe396d9614a12a302122022-12-21T17:01:00ZengBMCParasites & Vectors1756-33052020-10-0113111410.1186/s13071-020-04397-4Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistanceZhiwan Zheng0Jianping Chen1Guangxu Ma2Abhay R. Satoskar3Jiao Li4Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityDepartment of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityCollege of Animal Sciences, Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, Zhejiang UniversityDepartment of Pathology, Ohio State University Medical Center, Ohio State UniversityDepartment of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityAbstract Background Leishmaniasis is a neglected tropical disease affecting millions of people worldwide. Emerging drug resistance of Leishmania species poses threaten to the effective control and elimination programme of this neglected tropical disease. Methods In this work, we conducted drug-resistance testing, whole genome resequencing and proteome profiling for a recently reported clinical isolate with supposed drug resistance (HCZ), and two reference sensitive strains (DD8 and 9044) of Leishmania donovani, to explore molecular mechanisms underlying drug resistance in this parasite. Results With reference to DD8 and 9044 strains, HCZ isolate showed higher-level virulence and clear resistance to antimonials in promastigote culture, infected macrophages and animal experiment. Pairwise genomic comparisons revealed genetic variations (86 copy number variations, 271 frameshift mutations in protein-coding genes and two site mutations in non-coding genes) in HCZ isolate that were absent from the reference sensitive strains. Proteomic analysis indicated different protein expression between HCZ isolate and reference strains, including 69 exclusively detected proteins and 82 consistently down-/upregulated molecules in the HCZ isolate. Integrative analysis showed linkage of 12 genomic variations (gene duplication, insertion and deletion) and their protein expression changes in HCZ isolate, which might be associated with pathogenic and antimony-resistant phenotype. Functional annotation analyses further indicated that molecules involved in nucleotide-binding, fatty acid metabolism, oxidation-reduction and transport might play a role in host-parasite interaction and drug-resistance. Conclusions This comprehensive integrative work provided novel insights into the genetic basis underlying virulence and resistance, suggesting new aspects to be investigated for a better intervention against L. donovani and associated diseases.http://link.springer.com/article/10.1186/s13071-020-04397-4Leishmania donovaniAntimony resistanceWhole genome resequencingProteome profilingGenetic variations |
| spellingShingle | Zhiwan Zheng Jianping Chen Guangxu Ma Abhay R. Satoskar Jiao Li Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance Parasites & Vectors Leishmania donovani Antimony resistance Whole genome resequencing Proteome profiling Genetic variations |
| title | Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance |
| title_full | Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance |
| title_fullStr | Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance |
| title_full_unstemmed | Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance |
| title_short | Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance |
| title_sort | integrative genomic proteomic and phenotypic studies of leishmania donovani strains revealed genetic features associated with virulence and antimony resistance |
| topic | Leishmania donovani Antimony resistance Whole genome resequencing Proteome profiling Genetic variations |
| url | http://link.springer.com/article/10.1186/s13071-020-04397-4 |
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