Transcriptional differentiation of Trypanosoma brucei during in vitro acquisition of resistance to acoziborole

Autor: Kathryn Crouch, Fiona Achcar, Federica Giordani, Annette MacLeod, Isabel M. Vincent, Pieter C. Steketee, Michael P. Barrett, Liam J. Morrison, Nicholas J. Dickens
Jazyk: angličtina
Rok vydání: 2021
Předmět:
RC955-962
Drug Resistance
Protozoan Proteins
Transcriptome
0302 clinical medicine
Medical Conditions
Drug Metabolism
Arctic medicine. Tropical medicine
Zoonoses
Medicine and Health Sciences
African trypanosomiasis
Procyclin
Protozoans
0303 health sciences
biology
Eukaryota
Gene Expression Regulation
Developmental
Genomics
Phenotype
Trypanocidal Agents
3. Good health
Cell biology
Infectious Diseases
Public aspects of medicine
RA1-1270
Transcriptome Analysis
Research Article
Neglected Tropical Diseases
Trypanosoma
Cell Physiology
Trypanosoma brucei brucei
Trypanosoma brucei
Research and Analysis Methods
African Trypanosomiasis
03 medical and health sciences
Sinefungin
Trypanosomiasis
medicine
Trypanosoma Brucei
Genetics
Parasitic Diseases
Humans
Pharmacokinetics
Molecular Biology Techniques
Gene
Molecular Biology
030304 developmental biology
Pharmacology
Life Cycle Stages
Protozoan Infections
Gene Expression Profiling
Public Health
Environmental and Occupational Health
Organisms
Biology and Life Sciences
Computational Biology
Cell Biology
biology.organism_classification
medicine.disease
Genome Analysis
Tropical Diseases
Parasitic Protozoans
Cell Metabolism
Trypanosomiasis
African
030217 neurology & neurosurgery
Trypanosoma Brucei Gambiense
Cloning
Zdroj: PLoS Neglected Tropical Diseases
PLoS Neglected Tropical Diseases, Vol 15, Iss 11, p e0009939 (2021)
Steketee, P, Giordani, F, Vincent, I M, Crouch, K, Achcar, F, Dickens, N J, Morrison, L, MacLeod, A & Barrett, M P 2021, ' 'Transcriptional differentiation of Trypanosoma brucei during in vitro acquisition of resistance to acoziborole ', PLoS Neglected Tropical Diseases, vol. 15, no. 11, e0009939 . https://doi.org/10.1371/journal.pntd.0009939
ISSN: 1935-2735
1935-2727
Popis: Subspecies of the protozoan parasite Trypanosoma brucei 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 in vitro-derived acoziborole-resistant 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 in vitro can be accompanied by transcriptomic switches resembling a procyclic- or stumpy-type phenotype.
Author summary Human African Trypanosomiasis (HAT), also known as Sleeping Sickness, is a parasitic disease prevalent across sub-Saharan Africa, where it is transmitted by blood-sucking Tsetse flies. The disease is caused by a single-celled protozoan parasite called Trypanosoma brucei. HAT case numbers have decreased over the past two decades, and elimination is in sight. However, to meet the WHO objective of sustainable HAT elimination, newer and safer drugs are needed. Acoziborole is a new drug that has proven safe and effective against HAT and, unlike previous drugs, it can be orally administered. Whilst the mode of action of acoziborole was recently identified, less is known regarding the mechanisms by which T. brucei could become resistant to acoziborole. To address this, we generated a drug resistant cell line under laboratory conditions, in order to analyse the differences between resistant and sensitive cells. By sequencing the transcriptome, we observed that many genes associated with mammalian-infective parasites are down-regulated, whilst genes associated with the insect stage are up-regulated. As a result of these differences, the metabolic effects of acoziborole on parasites are nullified. These data suggest that parasite differentiation, albeit on a gene expression level, is potentially a mechanism of drug resistance in T. brucei, although it is doubtful whether this mechanism could occur in the field where mammalian immune effectors would destroy parasites differentiating this way.
Databáze: OpenAIRE
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