scholarly journals A Tale of Three Species: Adaptation ofSodalis glossinidiusto Tsetse Biology,WigglesworthiaMetabolism, and Host Diet

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Rebecca J. Hall ◽  
Lindsey A. Flanagan ◽  
Michael J. Bottery ◽  
Vicki Springthorpe ◽  
Stephen Thorpe ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
Strong Dependence ◽  
Tsetse Fly ◽  
Disease Spread ◽  
Growth Media ◽  
Insect Vector ◽  
African Trypanosomiasis ◽  
Content Type ◽  
Sodalis Glossinidius

ABSTRACTThe tsetse fly is the insect vector for theTrypanosoma bruceiparasite, the causative agent of human African trypanosomiasis. The colonization and spread of the trypanosome correlate positively with the presence of a secondary symbiotic bacterium,Sodalis glossinidius. The metabolic requirements and interactions of the bacterium with its host are poorly understood, and herein we describe a metabolic model ofS. glossinidiusmetabolism. The model enabled the design and experimental verification of a defined medium that supportsS. glossinidiusgrowthex vivo. This has been used subsequently to analyzein vitroaspects ofS. glossinidiusmetabolism, revealing multiple unique adaptations of the symbiont to its environment. Continued dependence on a sugar, and the importance of the chitin monomerN-acetyl-d-glucosamine as a carbon and energy source, suggests adaptation to host-derived molecules. Adaptation to the amino acid-rich blood diet is revealed by a strong dependence onl-glutamate as a source of carbon and nitrogen and by the ability to rescue a predictedl-arginine auxotrophy. Finally, the selective loss of thiamine biosynthesis, a vitamin provided to the host by the primary symbiontWigglesworthia glossinidia, reveals an intersymbiont dependence. The reductive evolution ofS. glossinidiusto exploit environmentally derived metabolites has resulted in multiple weaknesses in the metabolic network. These weaknesses may become targets for reagents that inhibitS. glossinidiusgrowth and aid the reduction of trypanosomal transmission.IMPORTANCEHuman African trypanosomiasis is caused by theTrypanosoma bruceiparasite. The tsetse fly vector is of interest for its potential to prevent disease spread, as it is essential forT. bruceilife cycle progression and transmission. The tsetse’s mutualistic endosymbiontSodalis glossinidiushas a link to trypanosome establishment, providing a disease control target. Here, we describe a new, experimentally verified model ofS. glossinidiusmetabolism. This model has enabled the development of a defined growth medium that was used successfully to test aspects ofS. glossinidiusmetabolism. We presentS. glossinidiusas uniquely adapted to life in the tsetse, through its reliance on the blood diet and host-derived sugars. Additionally,S. glossinidiushas adapted to the tsetse’s obligate symbiontWigglesworthia glossinidiaby scavenging a vitamin it produces for the insect. This work highlights the use of metabolic modeling to design defined growth media for symbiotic bacteria and may provide novel inhibitory targets to block trypanosome transmission.

scholarly journals Human african trypanosomiasis: current standing and challenges

2020 ◽  
Vol 49 (3) ◽  
Author(s):  
Isabel Theresa Holanda-Freitas ◽  
Marli Do Carmo Cupertino ◽  
Elizária C. dos Santos ◽  
Lisa Oliveira ◽  
Mauro Geller ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
Vaccine Development ◽  
Neglected Tropical Diseases ◽  
Tsetse Fly ◽  
World Health ◽  
Clinical Aspects ◽  
Neglected Diseases ◽  
African Trypanosomiasis ◽  
African Countries

Human African trypanosomiasis (HAT) caused by the protozoan Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, and transmitted by the tsetse fly (genus Glossina), affects 36 Sub-Saharan African countries with considerable public health impact.  Despite approximately 15,000 infected individuals and 70 million at risk, in recent years the World Health Organization has mentioned removal of HAT from the list of Neglected Tropical Diseases by 2020, due to the decrease in cases over the last two decades. When untreated, the disease presents high lethality rates and the available treatments are complicated to administer, highly toxic, and do not guarantee cure, especially in the advanced stages of the disease. Further, there is no prospect for vaccine development in the near future. The present review compiles information on the history of the clinical aspects of HAT, as well as its epidemiology, diagnosis, therapy, and prophylaxis, as well as updating information on the current panorama and perspectives regarding the disease.KEY WORDS: African Trypanosomiasis; neglected diseases; Trypanosoma brucei.

scholarly journals Glycolysis in the African Trypanosome: Targeting Enzymes and Their Subcellular Compartments for Therapeutic Development

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
April F. Coley ◽  
Heidi C. Dodson ◽  
Meredith T. Morris ◽  
James C. Morris
Keyword(s):  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
Tsetse Fly ◽  
Insect Vector ◽  
African Trypanosome ◽  
Atp Production ◽  
Human Host ◽  
Subcellular Compartments ◽  
Therapeutic Development ◽  
Cellular Components

Subspecies of the African trypanosome, Trypanosoma brucei, which cause human African trypanosomiasis, are transmitted by the tsetse fly, with transmission-essential lifecycle stages occurring in both the insect vector and human host. During infection of the human host, the parasite is limited to using glycolysis of host sugar for ATP production. This dependence on glucose breakdown presents a series of targets for potential therapeutic development, many of which have been explored and validated as therapeutic targets experimentally. These include enzymes directly involved in glucose metabolism (e.g., the trypanosome hexokinases), as well as cellular components required for development and maintenance of the essential subcellular compartments that house the major part of the pathway, the glycosomes.

scholarly journals Pharmacokinetics, Trypanosoma brucei gambiense Efficacy, and Time of Drug Action of DB829, a Preclinical Candidate for Treatment of Second-Stage Human African Trypanosomiasis

2013 ◽  
Vol 57 (11) ◽  
pp. 5330-5343 ◽  
Author(s):  
Tanja Wenzler ◽  
Sihyung Yang ◽  
Olivier Braissant ◽  
David W. Boykin ◽  
Reto Brun ◽  
...  
Keyword(s):  
Single Dose ◽  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
Drug Action ◽  
African Trypanosomiasis ◽  
Content Type ◽  
Second Stage ◽  
Trypanosoma Brucei Gambiense

ABSTRACTHuman African trypanosomiasis (HAT, also called sleeping sickness), a neglected tropical disease endemic to sub-Saharan Africa, is caused by the parasitesTrypanosoma brucei gambienseandT. brucei rhodesiense. Current drugs against this disease have significant limitations, including toxicity, increasing resistance, and/or a complicated parenteral treatment regimen. DB829 is a novel aza-diamidine that demonstrated excellent efficacy in mice infected withT. b. rhodesienseorT. b. bruceiparasites. The current study examined the pharmacokinetics,in vitroandin vivoactivity againstT. b. gambiense, and time of drug action of DB829 in comparison to pentamidine. DB829 showed outstandingin vivoefficacy in mice infected with parasites ofT. b. gambiensestrains, despite having higherin vitro50% inhibitory concentrations (IC50s) than againstT. b. rhodesiensestrain STIB900. A single dose of DB829 administered intraperitoneally (5 mg/kg of body weight) cured all mice infected with differentT. b. gambiensestrains. No cross-resistance was observed between DB829 and pentamidine inT. b. gambiensestrains isolated from melarsoprol-refractory patients. Compared to pentamidine, DB829 showed a greater systemic exposure when administered intraperitoneally, partially contributing to its improved efficacy. Isothermal microcalorimetry andin vivotime-to-kill studies revealed that DB829 is a slower-acting trypanocidal compound than pentamidine. A single dose of DB829 (20 mg/kg) administered intraperitoneally clears parasites from mouse blood within 2 to 5 days. In summary, DB829 is a promising preclinical candidate for the treatment of first- and second-stage HAT caused by bothTrypanosoma bruceisubspecies.

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.

New Pd-Fe ferrocenyl antiparasitic compounds with bioactive 8-hydroxyquinoline ligands: a comparative study with their Pt-Fe analogues

2021 ◽  
Author(s):  
Feriannys Rivas ◽  
Andrea Medeiros ◽  
Cristina Quiroga ◽  
Diego Benítez ◽  
Marcelo Comini ◽  
...  
Keyword(s):  
Comparative Study ◽  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
African Trypanosomiasis

In the search for a more effective chemotherapy for the treatment of Human African Trypanosomiasis, the disease caused by the parasite Trypanosoma brucei, the development of ferrocenyl compounds has arisen...

scholarly journals Cross-Resistance to Nitro Drugs and Implications for Treatment of Human African Trypanosomiasis

2010 ◽  
Vol 54 (7) ◽  
pp. 2893-2900 ◽  
Author(s):  
Antoaneta Y. Sokolova ◽  
Susan Wyllie ◽  
Stephen Patterson ◽  
Sandra L. Oza ◽  
Kevin D. Read ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
Parent Drug ◽  
Cross Resistance ◽  
Pharmacokinetic Studies ◽  
African Trypanosomiasis ◽  
Trypanosoma Brucei Brucei ◽  
Resistant Lines

ABSTRACT The success of nifurtimox-eflornithine combination therapy (NECT) for the treatment of human African trypanosomiasis (HAT) has renewed interest in the potential of nitro drugs as chemotherapeutics. In order to study the implications of the more widespread use of nitro drugs against these parasites, we examined the in vivo and in vitro resistance potentials of nifurtimox and fexinidazole and its metabolites. Following selection in vitro by exposure to increasing concentrations of nifurtimox, Trypanosoma brucei brucei nifurtimox-resistant clones designated NfxR1 and NfxR2 were generated. Both cell lines were found to be 8-fold less sensitive to nifurtimox than parental cells and demonstrated cross-resistance to a number of other nitro drugs, most notably the clinical trial candidate fexinidazole (∼27-fold more resistant than parental cells). Studies of mice confirmed that the generation of nifurtimox resistance in these parasites did not compromise virulence, and NfxR1 remained resistant to both nifurtimox and fexinidazole in vivo. In the case of fexinidazole, drug metabolism and pharmacokinetic studies indicate that the parent drug is rapidly metabolized to the sulfoxide and sulfone form of this compound. These metabolites retained trypanocidal activity but were less effective in nifurtimox-resistant lines. Significantly, trypanosomes selected for resistance to fexinidazole were 10-fold more resistant to nifurtimox than parental cells. This reciprocal cross-resistance has important implications for the therapeutic use of nifurtimox in a clinical setting and highlights a potential danger in the use of fexinidazole as a monotherapy.

Trypanosoma brucei: posttranscriptional control of the variable surface glycoprotein gene expression site

1989 ◽  
Vol 9 (9) ◽  
pp. 4018-4021
Author(s):  
E Pays ◽  
H Coquelet ◽  
A Pays ◽  
P Tebabi ◽  
M Steinert
Keyword(s):  
Gene Expression ◽  
Trypanosoma Brucei ◽  
Transcription Initiation ◽  
Tsetse Fly ◽  
Surface Glycoprotein ◽  
Insect Vector ◽  
Variable Surface Glycoprotein ◽  
A Genome ◽  
Variable Surface ◽  
Expression Site

The arrest of variable surface glycoprotein (VSG) synthesis is one of the first events accompanying the differentiation of Trypanosoma brucei bloodstream forms into procyclic forms, which are characteristic of the insect vector. This is because of a very fast inhibition of VSG gene transcription which occurs as soon as the temperature is lowered. We report that this effect is probably not controlled at the level of transcription initiation, since the beginning of the VSG gene expression site, about 45 kilobases upstream from the antigen gene, remains transcribed in procyclic forms. The permanent activity of the promoter readily accounts for the systematic reappearance, upon return to the bloodstream form after cyclical transmission, of the antigen type present before passage to the tsetse fly. The abortive transcription of the VSG gene expression site appears linked to RNA processing abnormalities. Such posttranscriptional controls may allow the modulation of gene expression in a genome organized in large multigenic transcription units.

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