scholarly journals The Occurrence of Malignancy in Trypanosoma brucei brucei by Rapid Passage in Mice

2022 ◽  
Vol 12 ◽  
Author(s):  
Xiao-Li Cai ◽  
Su-Jin Li ◽  
Peng Zhang ◽  
Ziyin Li ◽  
Geoff Hide ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Natural Phenomenon ◽  
Mammalian Host ◽  
Insect Vector ◽  
Differentiation Potential ◽  
Developmental Program ◽  
Transcriptional Changes ◽  
Eukaryotic Organisms ◽  
Qualitative Changes

Pleomorphic Trypanosoma brucei are best known for their tightly controlled cell growth and developmental program, which ensures their transmissibility and host fitness between the mammalian host and insect vector. However, after long-term adaptation in the laboratory or by natural evolution, monomorphic parasites can be derived. The origin of these monomorphic forms is currently unclear. Here, we produced a series of monomorphic trypanosome stocks by artificially syringe-passage in mice, creating snapshots of the transition from pleomorphism to monomorphism. We then compared these artificial monomorphic trypanosomes, alongside several naturally monomorphic T. evansi and T. equiperdum strains, with the pleomorphic T. brucei. In addition to failing to generate stumpy forms in animal bloodstream, we found that monomorphic trypanosomes from laboratory and nature exhibited distinct differentiation patterns, which are reflected by their distinct differentiation potential and transcriptional changes. Lab-adapted monomorphic trypanosomes could still be induced to differentiate, and showed only minor transcriptional differences to that of the pleomorphic slender forms but some accumulated differences were observed as the passages progress. All naturally monomorphic strains completely fail to differentiate, corresponding to their impaired differentiation regulation. We propose that the natural phenomenon of trypanosomal monomorphism is actually a malignant manifestation of protozoal cells. From a disease epidemiological and evolutionary perspective, our results provide evidence for a new way of thinking about the origin of these naturally monomorphic strains, the malignant evolution of trypanosomes may raise some concerns. Additionally, these monomorphic trypanosomes may reflect the quantitative and qualitative changes in the malignant evolution of T. brucei, suggesting that single-celled protozoa may also provide the most primitive model of cellular malignancy, which could be a primitive and inherent biological phenomenon of eukaryotic organisms from protozoans to mammals.

scholarly journals Metabolic reprogramming during the Trypanosoma brucei life cycle

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 683 ◽  
Author(s):  
Terry K. Smith ◽  
Frédéric Bringaud ◽  
Derek P. Nolan ◽  
Luisa M. Figueiredo
Keyword(s):  
Life Cycle ◽  
Trypanosoma Brucei ◽  
Model Organism ◽  
Protozoan Parasite ◽  
Tsetse Fly ◽  
Metabolic Reprogramming ◽  
Mammalian Host ◽  
Insect Vector ◽  
Environmental Signals ◽  
Cellular Metabolic Activity

Cellular metabolic activity is a highly complex, dynamic, regulated process that is influenced by numerous factors, including extracellular environmental signals, nutrient availability and the physiological and developmental status of the cell. The causative agent of sleeping sickness, Trypanosoma brucei, is an exclusively extracellular protozoan parasite that encounters very different extracellular environments during its life cycle within the mammalian host and tsetse fly insect vector. In order to meet these challenges, there are significant alterations in the major energetic and metabolic pathways of these highly adaptable parasites. This review highlights some of these metabolic changes in this early divergent eukaryotic model organism.

Metacyclic variant surface glycoprotein genes of Trypanosoma brucei subsp. rhodesiense are activated in situ, and their expression is transcriptionally regulated

1986 ◽  
Vol 6 (6) ◽  
pp. 1991-1997
Author(s):  
M J Lenardo ◽  
K M Esser ◽  
A M Moon ◽  
L H Van der Ploeg ◽  
J E Donelson
Keyword(s):  
Trypanosoma Brucei ◽  
Gene Deletion ◽  
Surface Glycoprotein ◽  
Mammalian Host ◽  
Small Subset ◽  
Insect Vector ◽  
Gradient Electrophoresis ◽  
Variant Surface Glycoproteins ◽  
Variant Antigen

During the metacyclic stage in the life cycle of Trypanosoma brucei subsp. rhodesiense, the expression of variant surface glycoproteins (VSGs) is restricted to a small subset of antigenic types. Previously we identified cDNAs for the VSGs expressed in metacyclic variant antigen types (MVATs) 4 and 7 and found that these VSG genes do not rearrange when expressed at the metacyclic stage (M. J. Lenardo, A. C. Rice-Ficht, G. Kelly, K. Esser, and J. E. Donelson, Proc. Nathl. Acad Sci. USA 81:6642-6646, 1984). We now provide further evidence that these genes do not rearrange and demonstrate that their 5' upstream regions lack the 72 to 76-base-pair repeats which are considered the substrate for duplication and transposition events. Pulsed field gradient electrophoresis showed that the MVAT VSG genes were located on the largest chromosome-sized DNA molecules, and the lack of the MVAT 4 gene in one of two different serodemes suggested that one mechanism for the evolution of MVAT repertoires is gene deletion. When MVATs were inoculated into the bloodstream of a mammalian host by a bite from the insect vector, they rapidly switched into nonmetacyclic VSG types. We found that this switch was accomplished by a loss of MVAT RNA concomitant with the loss of metacyclic VSGs. Transcription studies with isolated metacyclic nuclei showed that the MVAT genes were expressed in situ from a single locus and were regulated at the level of transcription.

scholarly journals Investigating the Chaperone Properties of a Novel Heat Shock Protein, Hsp70.c, fromTrypanosoma brucei

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Adélle Burger ◽  
Michael H. Ludewig ◽  
Aileen Boshoff
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Trypanosoma Brucei ◽  
Mammalian Host ◽  
Insect Vector ◽  
Wide Range ◽  
Response To Stress ◽  
Parasite Biology ◽  
Substrate Binding Domain

The neglected tropical disease, African Trypanosomiasis, is fatal and has a crippling impact on economic development. Heat shock protein 70 (Hsp70) is an important molecular chaperone that is expressed in response to stress and Hsp40 acts as its co-chaperone. These proteins play a wide range of roles in the cell and they are required to assist the parasite as it moves from a cold blooded insect vector to a warm blooded mammalian host. A novel cytosolic Hsp70, fromTrypanosoma brucei, TbHsp70.c, contains an acidic substrate binding domain and lacks the C-terminal EEVD motif. The ability of a cytosolic Hsp40 fromTrypanosoma bruceiJ protein 2, Tbj2, to function as a co-chaperone of TbHsp70.c was investigated. The main objective was to functionally characterize TbHsp70.c to further expand our knowledge of parasite biology. TbHsp70.c and Tbj2 were heterologously expressed and purified and both proteins displayed the ability to suppress aggregation of thermolabile MDH and chemically denatured rhodanese. ATPase assays revealed a 2.8-fold stimulation of the ATPase activity of TbHsp70.c by Tbj2. TbHsp70.c and Tbj2 both demonstrated chaperone activity and Tbj2 functions as a co-chaperone of TbHsp70.c.In vivoheat stress experiments indicated upregulation of the expression levels of TbHsp70.c.

scholarly journals Apoptosis in Trypanosomatids: Evolutionary and phylogenetic considerations

1998 ◽  
Vol 21 (1) ◽  
pp. 21-24 ◽  
Author(s):  
Marcello A. Barcinski
Keyword(s):  
Cell Death ◽  
Normal Tissue ◽  
Evolutionary Origin ◽  
Mammalian Host ◽  
Insect Vector ◽  
Developmental Program ◽  
Unicellular Organisms ◽  
Multicellular Organisms ◽  
Organizational Needs ◽  
Experimental Strategies

Programmed cell death (PCD) or apoptosis, an active process of cell death, plays a central role in normal tissue development and organogenesis, as well as in the pathogenesis of different diseases. Although it occurs in diverse cells and tissues under the influence of a remarkable variety of inducing agents, the resultant ultrastructural and biochemical changes are extremely monotonous, indicating the existence of a common biological mechanism underlying its occurrence. It is generally accepted that a developmental program leading to cell death cannot be advantageous to unicellular organisms and that PCD appeared in evolution to fulfill the organizational needs of multicellular life. However, the recent description of apoptotic death occurring in three different species of pathogenic kinetoplastids suggests that the evolutionary origin of PCD precedes the appearence of multicellular organisms. The present study proposes that a population of pathogenic Trypanosomatids is socially organized and that PCD is a prerequisite for this organization and for the fulfillment of the demands of a heteroxenic lifestyle. This proposal includes possible roles for PCD in the development of the parasite in the insect vector and/or in its mammalian host and suggests experimental strategies to localize the evolutionary origin of PCD within the kinetoplastids.

scholarly journals Procyclin gene expression and loss of the variant surface glycoprotein during differentiation of Trypanosoma brucei.

1989 ◽  
Vol 108 (2) ◽  
pp. 737-746 ◽  
Author(s):  
I Roditi ◽  
H Schwarz ◽  
T W Pearson ◽  
R P Beecroft ◽  
M K Liu ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Tsetse Fly ◽  
Surface Glycoprotein ◽  
Variant Surface Glycoprotein ◽  
Mammalian Host ◽  
Cylindrical Shape ◽  
Surface Coat ◽  
Insect Vector ◽  
Molecular Arrangement

In the mammalian host, the unicellular flagellate Trypanosoma brucei is covered by a dense surface coat that consists of a single species of macromolecule, the membrane form of the variant surface glycoprotein (mfVSG). After uptake by the insect vector, the tsetse fly, bloodstream-form trypanosomes differentiate to procyclic forms in the fly midgut. Differentiation is characterized by the loss of the mfVSG coat and the acquisition of a new surface glycoprotein, procyclin. In this study, the change in surface glycoprotein composition during differentiation was investigated in vitro. After triggering differentiation, a rapid increase in procyclin-specific mRNA was observed. In contrast, there was a lag of several hours before procyclin could be detected. Procyclin was incorporated and uniformly distributed in the surface coat. The VSG coat was subsequently shed. For a single cell, it took 12-16 h to express a maximum level of procyclin at the surface while the loss of the VSG coat required approximately 4 h. The data are discussed in terms of the possible molecular arrangement of mfVSG and procyclin at the cell surface. Molecular modeling data suggest that a (Asp-Pro)2 (Glu-Pro)22-29 repeat in procyclin assumes a cylindrical shape 14-18 nm in length and 0.9 nm in diameter. This extended shape would enable procyclin to interdigitate between the mfVSG molecules during differentiation, exposing epitopes beyond the 12-15-nm-thick VSG coat.

scholarly journals Metabolic reprogramming during the Trypanosoma brucei life cycle

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 683 ◽  
Author(s):  
Terry K. Smith ◽  
Frédéric Bringaud ◽  
Derek P. Nolan ◽  
Luisa M. Figueiredo
Keyword(s):  
Life Cycle ◽  
Trypanosoma Brucei ◽  
Model Organism ◽  
Protozoan Parasite ◽  
Tsetse Fly ◽  
Metabolic Reprogramming ◽  
Mammalian Host ◽  
Insect Vector ◽  
Environmental Signals ◽  
Cellular Metabolic Activity

Cellular metabolic activity is a highly complex, dynamic, regulated process that is influenced by numerous factors, including extracellular environmental signals, nutrient availability and the physiological and developmental status of the cell. The causative agent of sleeping sickness, Trypanosoma brucei, is an exclusively extracellular protozoan parasite that encounters very different extracellular environments during its life cycle within the mammalian host and tsetse fly insect vector. In order to meet these challenges, there are significant alterations in the major energetic and metabolic pathways of these highly adaptable parasites. This review highlights some of these metabolic changes in this early divergent eukaryotic model organism.

scholarly journals Metacyclic variant surface glycoprotein genes of Trypanosoma brucei subsp. rhodesiense are activated in situ, and their expression is transcriptionally regulated.

1986 ◽  
Vol 6 (6) ◽  
pp. 1991-1997 ◽  
Author(s):  
M J Lenardo ◽  
K M Esser ◽  
A M Moon ◽  
L H Van der Ploeg ◽  
J E Donelson
Keyword(s):  
Trypanosoma Brucei ◽  
Gene Deletion ◽  
Surface Glycoprotein ◽  
Mammalian Host ◽  
Small Subset ◽  
Insect Vector ◽  
Gradient Electrophoresis ◽  
Variant Surface Glycoproteins ◽  
Variant Antigen

During the metacyclic stage in the life cycle of Trypanosoma brucei subsp. rhodesiense, the expression of variant surface glycoproteins (VSGs) is restricted to a small subset of antigenic types. Previously we identified cDNAs for the VSGs expressed in metacyclic variant antigen types (MVATs) 4 and 7 and found that these VSG genes do not rearrange when expressed at the metacyclic stage (M. J. Lenardo, A. C. Rice-Ficht, G. Kelly, K. Esser, and J. E. Donelson, Proc. Nathl. Acad Sci. USA 81:6642-6646, 1984). We now provide further evidence that these genes do not rearrange and demonstrate that their 5' upstream regions lack the 72 to 76-base-pair repeats which are considered the substrate for duplication and transposition events. Pulsed field gradient electrophoresis showed that the MVAT VSG genes were located on the largest chromosome-sized DNA molecules, and the lack of the MVAT 4 gene in one of two different serodemes suggested that one mechanism for the evolution of MVAT repertoires is gene deletion. When MVATs were inoculated into the bloodstream of a mammalian host by a bite from the insect vector, they rapidly switched into nonmetacyclic VSG types. We found that this switch was accomplished by a loss of MVAT RNA concomitant with the loss of metacyclic VSGs. Transcription studies with isolated metacyclic nuclei showed that the MVAT genes were expressed in situ from a single locus and were regulated at the level of transcription.

scholarly journals The Hsp90 chaperone system from the African trypanosome, Trypanosoma brucei

2021 ◽  
Author(s):  
Aileen Boshoff ◽  
Miebaka Jamabo ◽  
Stephen J Bentley ◽  
Paula Macucule-Tinga ◽  
Adrienne Edkins
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Trypanosoma Brucei ◽  
Molecular Chaperones ◽  
Sub Saharan Africa ◽  
Mammalian Host ◽  
Insect Vector ◽  
Single Chromosome ◽  
African Trypanosome ◽  
Shock Proteins

African Trypanosomiasis is a neglected tropical disease caused by Trypanosoma brucei ( T. brucei ) and is spread by the tsetse fly in sub-Saharan Africa. The disease is fatal if left untreated and the currently approved drugs for treatment are toxic and difficult to administer. The trypanosome must survive in the insect vector and its mammalian host, and to adapt to these different conditions, the parasite relies on molecular chaperones called heat shock proteins. Heat shock proteins mediate the folding of newly synthesized proteins as well as prevent misfolding of proteins under normal conditions and during stressful conditions. Heat shock protein 90 (Hsp90) is one of the major molecular chaperones of the stress response at the cellular level. It functions with other chaperones and co-chaperones and inhibition of its interactions is being explored as a potential therapeutic target for numerous diseases. This study provides an in-silico overview of Hsp90 and its co-chaperones in both T. brucei brucei and T. brucei gambiense in relation to human and other kinetoplastid parasites . The evolutionary, functional, and structural analyses of Hsp90 were also shown. The updated information on Hsp90 and its co-chaperones from recently published proteomics on T. brucei was examined for the different life cycle stages and subcellular localisations. The results show a difference between T. b. brucei and T. b. gambiense with T. b. brucei encoding 12 putative Hsp90 genes, 10 of which are cytosolic and located on a single chromosome while T. gambiense encodes 5 Hsp90 genes, 3 of which are located in the cytosol. Eight putative co-chaperones were identified in this study, 6 TPR-containing and 2 non-TPR-containing co-chaperones. This study provides an updated context for studying the biology of the African trypanosome and evaluating Hsp90 and its interactions as potential drug targets.

scholarly journals Polysomal mRNA Association and Gene Expression in Trypanosoma brucei

2021 ◽  
Vol 6 ◽  
pp. 36
Author(s):  
Michele Tinti ◽  
Anna Kelner-Mirôn ◽  
Lizzie J. Marriott ◽  
Michael A.J. Ferguson
Keyword(s):  
Gene Expression ◽  
Trypanosoma Brucei ◽  
Regulation Of Gene Expression ◽  
Mammalian Host ◽  
General Interest ◽  
Insect Vector ◽  
Rna Seq ◽  
Protein Coding ◽  
Polysomal Mrna ◽  
Non Coding Rnas

Background: The contrasting physiological environments of Trypanosoma brucei procyclic (insect vector) and bloodstream (mammalian host) forms necessitates deployment of different molecular processes and, therefore, changes in protein expression. Transcriptional regulation is unusual in T. brucei because the arrangement of genes is polycistronic; however, genes which are transcribed together are subsequently cleaved into separate mRNAs by trans-splicing. Following pre-mRNA processing, the regulation of mature mRNA stability is a tightly controlled cellular process. While many stage-specific transcripts have been identified, previous studies using RNA-seq suggest that changes in overall transcript level do not necessarily reflect the abundance of the corresponding protein. Methods: To better understand the regulation of gene expression in T. brucei, we performed a bioinformatic analysis of RNA-seq on total, sub-polysomal, and polysomal mRNA samples. We further cross-referenced our dataset with a previously published proteomics dataset to identify new protein coding sequences. Results: Our analyses showed that several long non-coding RNAs are more abundant in the sub-polysome samples, which possibly implicates them in regulating cellular differentiation in T. brucei. We also improved the annotation of the T.brucei genome by identifying new putative protein coding transcripts that were confirmed by mass spectrometry data. Conclusions: Several long non-coding RNAs are more abundant in the sub-polysome cellular fractions and might pay a role in the regulation of gene expression. We hope that these data will be of wide general interest, as well as being of specific value to researchers studying gene regulation expression and life stage transitions in T. brucei.

Genetic variation in Trypanosoma brucei and the epidemiology of sleeping sickness in the Lambwe Valley, Kenya

Parasitology ◽  
1992 ◽  
Vol 104 (1) ◽  
pp. 99-109 ◽  
Author(s):  
R. E. Cibulskis
Keyword(s):  
Trypanosoma Brucei ◽  
Host Species ◽  
Major Change ◽  
Sleeping Sickness ◽  
Genetic Exchange ◽  
Mammalian Host ◽  
Exchange Sex ◽  
Geographical Distances ◽  
Lambwe Valley

SUMMARYA contingency table approach was used to explore the influence of location, host species and time on the genetic composition of a Trypanosoma brucei population in Lambwe Valley, Kenya. Significant differences in zymodeme frequencies were noticed over comparatively short geographical distances suggesting that transmission of T. brucei is somewhat localized. A significant association was observed between zymodeme and the mammalian host from which T. brucei was derived. The association was consistent in different localities in Lambwe valley and remained stable for at least 32 months. These observations indicate that zymodemes are adapted to different host species and that genetic exchange has not disrupted host associations over this time-scale. A major change in the composition of the T. brucei population during a sleeping sickness outbreak in 1980 was confirmed. But while new zymodemes emerged, a decline in overall diversity was noted during times of high sleeping sickness incidence. The results can be explained by selection of T. brucei zymodemes for particular transmission cycles. Although it is not necessary to invoke genetic exchange, sex may help T. brucei to adapt to changes in selection pressures. Such a hypothesis helps to explain why T. brucei appears largely clonal in the short term, even though population studies indicate that sex is responsible for much genetic diversity in the long term. It also explains why neighbouring populations of T. brucei are composed of a different range of zymodemes formed from the same alleles. Such a view implies that genetic exchange has an important role in the microevolution of T. brucei populations.

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