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Leishmania Donovani Strains Revealed Genetic Features Associated with Virulence and Antimony‑Resistance Zhiwan Zheng1, Jianping Chen1,2, Guangxu Ma3,4, Abhay R

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Leishmania Donovani Strains Revealed Genetic Features Associated with Virulence and Antimony‑Resistance Zhiwan Zheng1, Jianping Chen1,2, Guangxu Ma3,4, Abhay R Zheng et al. Parasites Vectors (2020) 13:510 https://doi.org/10.1186/s13071-020-04397-4 Parasites & Vectors RESEARCH Open Access Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance Zhiwan Zheng1, Jianping Chen1,2, Guangxu Ma3,4, Abhay R. Satoskar5,6 and Jiao Li1* Abstract Background: Leishmaniasis is a neglected tropical disease afecting millions of people worldwide. Emerging drug resistance of Leishmania species poses threaten to the efective control and elimination programme of this neglected tropical disease. Methods: In this work, we conducted drug-resistance testing, whole genome resequencing and proteome profling 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 diferent 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 viru- lence and resistance, suggesting new aspects to be investigated for a better intervention against L. donovani and associated diseases. Keywords: Leishmania donovani, Antimony resistance, Whole genome resequencing, Proteome profling, Genetic variations Background Leishmaniasis, a neglected tropical disease, is caused by the infection with Leishmania species, afecting millions of people in approximately 100 endemic countries [1, 2]. *Correspondence: [email protected] 1 Department of Pathogenic Biology, West China School of Basic Medical Tis parasitic disease is transmitted by the bite of phle- Sciences and Forensic Medicine, Sichuan University, Chengdu, China botomine sand fies, and have three main forms: cuta- Full list of author information is available at the end of the article neous, mucocutaneous and visceral leishmaniasis (VL) © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea- tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo- main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zheng et al. Parasites Vectors (2020) 13:510 Page 2 of 14 [3]. Although most people have a silent infection, some isolate (HCZ) and two drug-susceptible (DD8 and 9044) advanced cases of cutaneous leishmaniasis can cause strains of L. donovani. Comparative studies were per- ulcers, and VL is almost always fatal without proper formed to identify genetic variations and specifcities at treatment, especially the advanced one [3, 4]. In the past DNA and protein levels between the resistant and sus- decades, the intensive vector control and a better access ceptible phenotypes. Molecular mechanisms underlying to diagnosis and treatment facilities have successfully and virulence and resistance in L. donovani were explored substantially reduced the number of VL in Asia [2, 5–7]. by comparing and integrating the phenotypic features, However, leishmaniasis remains to be one of the poverty- genomic variations and proteomic diferences among related diseases in underprivileged countries and regions HCZ isolate, DD8 and 9044 strains. [1, 2, 8]. No vaccines are currently available for clinical use to prevent the infection and reinfection by Leishma- Methods nia species, although progress has been made in this feld Procurement of parasites, drugs, cell and animals [9–11]. Chemotherapy is still the frst-line option for the A Leishmania clinical isolate (MHOM/CN/2016/ treatment and elimination of Leishmania infection and SCHCZ) was obtained from bone marrow puncture fuid related diseases [12, 13]. of a VL patient at West China Hospital, Sichuan Uni- Drug resistance of Leishmania species usually results versity, China. Te patient was treated with 4 courses in treatment failure and relapse of leishmaniasis, posing of antimonials treatment and then relapsed. Te bone a considerable threaten to the efective control of this dis- marrow puncture fuid was obtained after the relapse, ease [14]. Although liposomal amphotericin B, miltefos- then inoculated with three laboratory golden hamsters ine and pentavalent antimonials have been widely used by intraperitoneal injection, 0.3 ml per hamster. Clini- for the treatment of VL in the past decades, an increase cal isolate (MHOM/CN/2016/SCHCZ) and reference of treatment failure and sequela of infection has been fre- sensitive strains (MHOM/CN/IN/80/DD8 and MHOH/ quently reported in recent years, particularly in endemic CN/90/9044) of L. donovani have been preserved and countries and regions (e.g. Nepal and Southeast Asia passaged in the golden hamsters. Livers and spleens of region) [15–18]. Unfortunately, molecular mechanisms sick golden hamsters were homogenized and maintained underlying the establishment of drug resistance have not in M199 medium (Sigma-Aldrich St. Louis, MO, USA) yet been clearly elucidated [19], which signifcantly hin- supplemented with 10% fetal bovine serum (FBS; Gibco, ders the discovery of novel intervention strategies (e.g. Franklin, TN, USA) and antibiotics (100 U/ml penicillin new drugs or vaccines), and challenges the elimination and 100 μg/ml streptomycin; Hyclone, Logan, UT, USA) of leishmaniasis by 2020 in endemic areas. Tackling these at pH 7.4 and 28 °C for 5–7 days to culture promastigotes. issues and challenges requires a better understanding of Sodium stibogluconate (SSG; MCE, Monmouth Junc- the molecular basis underlying drug resistance in Leish- tion, NJ, USA) and potassium antimonyl tartrate trihy- mania species. drate (PAT; Sigma-Aldrich St. Louis, MO, USA) were In the past 30 years, progress has been made in unrav- dissolved in ultrapure water for a stock concentration elling the infection, genetics and evolution of Leishma- of 10 mM. A murine macrophage stable cell line RAW nia spp. at the molecular level [20–22]. Decoding the 264.7 (Jennio, Guangzhou, China) was recovered and genomes of Leishmania species marked an important maintained according to the manufacturer’s instructions. turning point for the molecular exploration of these path- Golden hamsters (Mesocricetus auratus, 8–10 weeks- ogens [23–25]. Particularly, recent genomic and tran- old, female) were purchased from the Chengdu Institute scriptomic studies of Leishmania species signifcantly of Biological Products Co., Ltd, Chengdu, China. Female advanced our understanding of the genetic plasticity and wild-type BALB/c mice aged 6–7 weeks were purchased molecular diferences between species/strains, which from Dassy (Experimental animals Co., Ltd, Chengdu, might be associated with the resistance to antileishma- China), and maintained under standard conditions. nial drugs and treatment failure [22, 26–29]. However, it is still challenging to integrate and interpret the genetic In vitro promastigote culture features revealed at DNA and RNA levels to elucidate the To test the likely antimony-resistance of the clinical iso- genetic basis for drug resistance in protozoan parasites. late (HCZ) of L. donovani [18], logarithmic phase pro- Clearly, there is a strong need to explore the genetic plas- mastigotes of HCZ isolate and reference sensitive strains ticity and biological variations of Leishmania species at DD8 and 9044 were harvested, washed, and cultured genomic and post-genomic (transcriptomic, proteomic in M199 medium (Sigma-Aldrich) supplemented with and metabolomic) levels [30, 31]. 10% FBS (Gibco), antibiotics (100 U/ml penicillin and In this study, we conducted antimony-resistant testing, 100 μg/ml streptomycin) and 65 μM of PAT (cf. [32]), 6 genomic sequencing and proteomic
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