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Genomic analysis of Isometamidium Chloride resistance in Trypanosoma congolense

ABSTRACT: Genomic analysis of Isometamidium Chloride resistance in Trypanosoma congolense

PROVIDER: PRJEB21066 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR5711970_1.fastq.gz	Fastqsanger.gz
	ERR5711970_2.fastq.gz	Fastqsanger.gz
	ERR5711980_1.fastq.gz	Fastqsanger.gz
	ERR5711980_2.fastq.gz	Fastqsanger.gz
	ERR5711971_1.fastq.gz	Fastqsanger.gz

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Project description:Purpose: The is a major paucity of knowledge regarding the biology of Trypanosoma congolense, a protozoan parasite primarily responsible for Animal African Trypanosomiasis. In contrast, the closely related species T. brucei, is far better understood. To characterise core metabolism in T. congolense, comparative RNAseq analysis was undertaken to assess similarities and differences in transcript levels of genes associated with metabolism Methods: Samples from both in vitro culture and ex vivo (isolated from murine infections) bloodstream-form T. brucei and T. congolense were RNA-sequenced. Data was analyzed using a pipeline that allows for inter-species comparison Results: T. congolense exhibits increased transcript abundance in genes associated with the glycosomal succinate shunt, as well as mitochondrial metabolism, in particular the catabolism of pyruvate to acetate, compared to T. brucei. These differences occur both in vitro and ex vivo. Furthermore there are differences in nucleotide metabolism, and transcript levels of genes involved in fatty acid synthesis are reduced in T. congolense compared to T. brucei. Conclusions: Comparative RNAseq between two closely related species provided a detailed overview of similarities and differences in core metabolism. This carries significant implications for adaptation to in vitro culture, and drug efficacy, mode of action and mode of resistance.

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Genomic analysis of Isometamidium Chloride resistance in Trypanosoma congolense.

Project description:Isometamidium Chloride (ISM) is one of the principal drugs used to counteract Trypanosoma congolense infection in livestock, both as a prophylactic as well as a curative treatment. However, numerous cases of ISM resistance have been reported in different African regions, representing a significant constraint in the battle against Animal African Trypanosomiasis. In order to identify genetic signatures associated with ISM resistance in T. congolense, the sensitive strain MSOROM7 was selected for induction of ISM resistance in a murine host. Administered ISM concentrations in immune-suppressed mice were gradually increased from 0.001 mg/kg to 1 mg/kg, the maximal dose used in livestock. As a result, three independent MSOROM7 lines acquired full resistance to this concentration after five months of induction, and retained this full resistant phenotype following a six months period without drug pressure. In contrast, parasites did not acquire ISM resistance in immune-competent animals, even after more than two years under ISM pressure, suggesting that the development of full ISM resistance is strongly enhanced when the host immune response is compromised. Genomic analyses comparing the ISM resistant lines with the parental sensitive line identified shifts in read depth at heterozygous loci in genes coding for different transporters and transmembrane products, and several of these shifts were also found within natural ISM resistant isolates. These findings suggested that the transport and accumulation of ISM inside the resistant parasites may be modified, which was confirmed by flow cytometry and ex vivo ISM uptake assays that showed a decrease in the accumulation of ISM in the resistant parasites.

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A conserved trypanosomatid differentiation regulator controls substrate attachment and morphological development in Trypanosoma congolense

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Triploid Trypanosoma congolense parasites

Project description:Evidence for viable and stable triploid Trypanosoma congolense parasites.

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Trypanosoma congolense strain:Tc1/148

Project description:Trypanosoma congolense strain:Tc1/148 Genome sequencing and assembly

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