Transcriptional differentiation of Trypanosoma brucei during in vitro acquisition of resistance to acoziborole
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ABSTRACT:
PROVIDER: PRJNA707209 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13870590_1.fastq.gz | Fastqsanger.gz | |||
| SRR13870590_2.fastq.gz | Fastqsanger.gz | |||
| SRR13870591_1.fastq.gz | Fastqsanger.gz | |||
| SRR13870591_2.fastq.gz | Fastqsanger.gz | |||
| SRR13870592_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Purpose: Acoziborole is a recently developed benzoxaborole class compound, currently in clinical trials, for stage 1 and stage 2 treatment of Human African Trypanosomiasis. Recent studies have made significant progress in determining the molecular mode of action of acoziborole. However, less is known about the potential mechanisms leading to acoziborole resistance in trypanosomes. By characterising in vitro drug-resistance, this study aimed to gain a better understanding of the mechanisms involved in acoziborole resistance in the clinicaly relevant Trypanosoma brucei Methods: Drug resistance was generated in vitro through incremental dosage of acoziborole. RNA was isolated from axenic cultures of drug-resistant and parental drug sensitive cells and submitted for RNA-seq Results: Transcriptomics analysis revealed widepread downregulation of transcripts associated with mammalian-infective bloodstream-form parasites. Conversely, transcripts associated with insect-stage procyclic form parasites were increased, indicating that the resistant cells had undergone an unspecified "differentiation event", albeit on a transcriptomic level Conclusions: Trypanosoma brucei resistance to acoziborole can be generated under in vitro axenic conditions, and "transcriptional differentiation" is a mechanism of resistance. However, it is unknown whether this phenomenon is relevant to an in vivo setting
2021-03-07 | GSE168394 | GEO
Project description:The host range of African trypanosomes is influenced by innate protective molecules in the blood of primates. A subfraction of human high-density lipoprotein (HDL) containing apolipoprotein A-I, apolipoprotein L-I, and haptoglobin-related protein is toxic to Trypanosoma brucei brucei but not the human sleeping sickness parasite Trypanosoma brucei rhodesiense. It is thought that T. b. rhodesiense evolved from a T. b. brucei-like ancestor and expresses a defense protein that ablates the antitrypanosomal activity of human HDL. To directly investigate this possibility, we developed an in vitro selection to generate human HDL-resistant T. b. brucei. Here we show that conversion of T. b. brucei from human HDL sensitive to resistant correlates with changes in the expression of the variant surface glycoprotein (VSG) and abolished uptake of the cytotoxic human HDLs. Complete transcriptome analysis of the HDL-susceptible and -resistant trypanosomes confirmed that VSG switching had occurred but failed to reveal the expression of other genes specifically associated with human HDL resistance, including the serum resistance-associated gene (SRA) of T. b. rhodesiense. In addition, we found that while the original active expression site was still utilized, expression of three expression site-associated genes (ESAG) was altered in the HDL-resistant trypanosomes. These findings demonstrate that resistance to human HDLs can be acquired by T. b. brucei. Keywords: Trypanosoma, VSG, antigenic switching, HDL-resistance
2007-07-04 | GSE8369 | GEO
Project description:In vitro generation of human high-density-lipoprotein-resistant Trypanosoma brucei brucei
| PRJNA101397 | ENA
Project description:<p>Subspecies of the protozoan parasite <em>Trypanosoma brucei</em> are the causative agents of Human African Trypanosomiasis (HAT), a debilitating neglected tropical disease prevalent across sub-Saharan Africa. HAT case numbers have steadily decreased since the start of the century, and sustainable elimination of one form of the disease is in sight. However, key to this is the development of novel drugs to combat the disease. Acoziborole is a recently developed benzoxaborole, currently in advanced clinical trials, for treatment of stage 1 and stage 2 HAT. Importantly, acoziborole is orally bioavailable, and curative with one dose. Recent studies have made significant progress in determining the molecular mode of action of acoziborole. However, less is known about the potential mechanisms leading to acoziborole resistance in trypanosomes. In this study, an <em>in vitro</em> derived acoziborole-resistant (AcoR) cell line was generated and characterised. The AcoR line exhibited significant cross-resistance with the methyltransferase inhibitor sinefungin as well as hypersensitisation to known trypanocides. Interestingly, transcriptomics analysis of AcoR cells indicated the parasites had obtained a procyclic- or stumpy-like transcriptome profile, with upregulation of procyclin surface proteins as well as differential regulation of key metabolic genes known to be expressed in a life cycle-specific manner, even in the absence of major morphological changes. However, no changes were observed in transcripts encoding CPSF3, the recently identified protein target of acoziborole. The results suggest that generation of resistance to this novel compound <em>in vitro</em> can be accompanied by transcriptomic switches resembling a procyclic- or stumpy-type phenotype.</p>
2021-11-02 | MTBLS2559 | MetaboLights
Project description:The host range of African trypanosomes is influenced by innate protective molecules in the blood of primates. A subfraction of human high-density lipoprotein (HDL) containing apolipoprotein A-I, apolipoprotein L-I, and haptoglobin-related protein is toxic to Trypanosoma brucei brucei but not the human sleeping sickness parasite Trypanosoma brucei rhodesiense. It is thought that T. b. rhodesiense evolved from a T. b. brucei-like ancestor and expresses a defense protein that ablates the antitrypanosomal activity of human HDL. To directly investigate this possibility, we developed an in vitro selection to generate human HDL-resistant T. b. brucei. Here we show that conversion of T. b. brucei from human HDL sensitive to resistant correlates with changes in the expression of the variant surface glycoprotein (VSG) and abolished uptake of the cytotoxic human HDLs. Complete transcriptome analysis of the HDL-susceptible and -resistant trypanosomes confirmed that VSG switching had occurred but failed to reveal the expression of other genes specifically associated with human HDL resistance, including the serum resistance-associated gene (SRA) of T. b. rhodesiense. In addition, we found that while the original active expression site was still utilized, expression of three expression site-associated genes (ESAG) was altered in the HDL-resistant trypanosomes. These findings demonstrate that resistance to human HDLs can be acquired by T. b. brucei. Keywords: Trypanosoma, VSG, antigenic switching, HDL-resistance Bloodstream stages of the Lister strain 427 T. b. brucei (MiTat 1.2), expressing VSG221, were used in these studies. Cells were cultured in HMI-9 medium with the addition of heat inactivated fetal bovine serum (FBS) (10%) and Serum Plus (10%). T. b. brucei 427-221 is an antigenically stable line and contains a single copy of the vsg221 gene within the 221 expression site (221ES). At a cell density of approximately 1,000,000 cells/ml, T. b. brucei 427-221 were exposed to various amounts of human HDLs for 24 h in a 6 well plate. Surviving trypanosomes were counted using a hemocytometer then diluted into fresh HMI-9 medium and allowed to recover for 5-14 days. Once the cells had grown to a density of approximately 1,000,000 cells/ml, they were once again incubated with human HDLs. Each round of selection was performed with increasing concentrations of human HDLs and freezer stocks were prepared for each surviving population. Over nine months we conducted eight rounds of human HDL selection, resulting in a population of T. b. brucei that survived incubation with 800 μl of human HDLs (160 lytic U).
2007-07-04 | E-GEOD-8369 | biostudies-arrayexpress
Project description:Trypanosoma brucei gambiense is the causative agent of the fatal human disease African sleeping sickness. Using Digital Gene Expression we have compared the transcriptome of a group 1 T.b.gambiense (Eliane) and a T.b.brucei (STIB 247).
2022-08-31 | GSE23885 | GEO
Project description:Trypanosoma brucei brucei edited mRNA transcriptomes
| PRJNA369536 | ENA
Project description:Trypanosoma brucei brucei Raw sequence reads
| PRJNA292451 | ENA