Abstract
BackgroundLeishmaniasis 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.MethodsIn 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.ResultsWith 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.ConclusionsThis 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.
Highlights
Leishmaniasis is a neglected tropical disease affecting millions of people worldwide
Lower number of intracellular amastigotes were observed in the macrophages infected with 9044 and DD8 strains after treatment (SSG, 10 μM), whereas more amastigotes were found in HCZ isolate infected macrophages (Fig. 2a)
Leishmania donovani HCZ isolate showed strong virulence and resistance in vivo To further confirm the antimony-resistant phenotype of HCZ isolate of L. donovani, resistance testing was conducted in a mice infection model
Summary
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. Leishmaniasis, a neglected tropical disease, is caused by the infection with Leishmania species, affecting millions of people in approximately 100 endemic countries [1, 2]. This parasitic disease is transmitted by the bite of phlebotomine sand flies, and have three main forms: cutaneous, mucocutaneous and visceral leishmaniasis (VL). Chemotherapy is still the first-line option for the treatment and elimination of Leishmania infection and related diseases [12, 13]
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