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 |
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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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