scholarly journals Survival of Trypanosoma brucei in the Tsetse Fly Is Enhanced by the Expression of Specific Forms of Procyclin

1997 ◽  
Vol 137 (6) ◽  
pp. 1369-1379 ◽  
Author(s):  
Stefan Ruepp ◽  
André Furger ◽  
Ursula Kurath ◽  
Christina Kunz Renggli ◽  
Andrew Hemphill ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Single Letter ◽  
Tsetse Fly ◽  
Insect Midgut ◽  
African Trypanosomes ◽  
Amino Acid Code ◽  
Successful Replication ◽  
Differentiation And Proliferation ◽  
Major Surface ◽  
Six Genes

African trypanosomes are not passively transmitted, but they undergo several rounds of differentiation and proliferation within their intermediate host, the tsetse fly. At each stage, the survival and successful replication of the parasites improve their chances of continuing the life cycle, but little is known about specific molecules that contribute to these processes. Procyclins are the major surface glycoproteins of the insect forms of Trypanosoma brucei. Six genes encode proteins with extensive glutamic acid–proline dipeptide repeats (EP in the single-letter amino acid code), and two genes encode proteins with an internal pentapeptide repeat (GPEET). To study the function of procyclins, we have generated mutants that have no EP genes and only one copy of GPEET. This last gene could not be replaced by EP procyclins, and could only be deleted once a second GPEET copy was introduced into another locus. The EP knockouts are morphologically indistinguishable from the parental strain, but their ability to establish a heavy infection in the insect midgut is severely compromised; this phenotype can be reversed by the reintroduction of a single, highly expressed EP gene. These results suggest that the two types of procyclin have different roles, and that the EP form, while not required in culture, is important for survival in the fly.

scholarly journals Unexpected plasticity in the life cycle of Trypanosoma brucei

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Sarah Schuster ◽  
Jaime Lisack ◽  
Ines Subota ◽  
Henriette Zimmermann ◽  
Christian Reuter ◽  
...  
Keyword(s):  
Life Cycle ◽  
Trypanosoma Brucei ◽  
Parasite Load ◽  
Tsetse Fly ◽  
Productive Infection ◽  
Complex Life Cycle ◽  
Chronic Infections ◽  
Population Densities ◽  
African Trypanosomes ◽  
Stage Transition

African trypanosomes cause sleeping sickness in humans and nagana in cattle. These unicellular parasites are transmitted by the bloodsucking tsetse fly. In the mammalian host's circulation, proliferating slender stage cells differentiate into cell cycle-arrested stumpy stage cells when they reach high population densities. This stage transition is thought to fulfil two main functions: first, it auto-regulates the parasite load in the host; second, the stumpy stage is regarded as the only stage capable of successful vector transmission. Here, we show that proliferating slender stage trypanosomes express the mRNA and protein of a known stumpy stage marker, complete the complex life cycle in the fly as successfully as the stumpy stage, and require only a single parasite for productive infection. These findings suggest a reassessment of the traditional view of the trypanosome life cycle. They may also provide a solution to a long-lasting paradox, namely the successful transmission of parasites in chronic infections, despite low parasitemia.

scholarly journals Expression site attenuation mechanistically links antigenic variation and development in Trypanosoma brucei

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Christopher Batram ◽  
Nicola G Jones ◽  
Christian J Janzen ◽  
Sebastian M Markert ◽  
Markus Engstler
Keyword(s):  
Trypanosoma Brucei ◽  
Histone Methylation ◽  
Antigenic Variation ◽  
Tsetse Fly ◽  
Developmental Competence ◽  
Surface Glycoprotein ◽  
G1 Phase ◽  
African Trypanosomes ◽  
Developmental Progression ◽  
Expression Site

We have discovered a new mechanism of monoallelic gene expression that links antigenic variation, cell cycle, and development in the model parasite Trypanosoma brucei. African trypanosomes possess hundreds of variant surface glycoprotein (VSG) genes, but only one is expressed from a telomeric expression site (ES) at any given time. We found that the expression of a second VSG alone is sufficient to silence the active VSG gene and directionally attenuate the ES by disruptor of telomeric silencing-1B (DOT1B)-mediated histone methylation. Three conserved expression-site-associated genes (ESAGs) appear to serve as signal for ES attenuation. Their depletion causes G1-phase dormancy and reversible initiation of the slender-to-stumpy differentiation pathway. ES-attenuated slender bloodstream trypanosomes gain full developmental competence for transformation to the tsetse fly stage. This surprising connection between antigenic variation and developmental progression provides an unexpected point of attack against the deadly sleeping sickness.

scholarly journals The polymorphic telomeres of the African trypanosome Trypanosoma brucei

2000 ◽  
Vol 28 (5) ◽  
pp. 536-540 ◽  
Author(s):  
G. Rudenko
Keyword(s):  
Trypanosoma Brucei ◽  
Surface Protein ◽  
Bloodstream Form ◽  
African Trypanosomes ◽  
African Trypanosome ◽  
Major Surface Protein ◽  
Genes Encoding ◽  
Expression Site ◽  
Major Surface

African trypanosomes have plastic genomes with extensive variability at the chromosome ends. The genes encoding the expressed major surface protein of the infective bloodstream form stages of Trypanosoma brucei and are located at telomeres. These telomeric expression-site transcription units are turning out to be surprisingly polymorphic in structure and sequence.

scholarly journals Oxidative Phosphorylation Is Required for Powering Motility and Development of the Sleeping Sickness Parasite Trypanosoma brucei in the Tsetse Fly Vector

mBio ◽  
2022 ◽  
Author(s):  
Caroline E. Dewar ◽  
Aitor Casas-Sanchez ◽  
Constentin Dieme ◽  
Aline Crouzols ◽  
Lee R. Haines ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Salivary Glands ◽  
Trypanosoma Brucei ◽  
Blood Meal ◽  
Sleeping Sickness ◽  
Tsetse Fly ◽  
Tsetse Flies ◽  
African Trypanosomes ◽  
Complex Development

African trypanosomes cause disease in humans and their livestock and are transmitted by tsetse flies. The insect ingests these parasites with its blood meal, but to be transmitted to another mammal, the trypanosome must undergo complex development within the tsetse fly and migrate from the insect's gut to its salivary glands.

scholarly journals Protein tyrosine phosphatase TbPTP1: a molecular switch controlling life cycle differentiation in trypanosomes

2006 ◽  
Vol 175 (2) ◽  
pp. 293-303 ◽  
Author(s):  
Balázs Szöőr ◽  
Jude Wilson ◽  
Helen McElhinney ◽  
Lydia Tabernero ◽  
Keith R. Matthews
Keyword(s):  
Life Cycle ◽  
Trypanosoma Brucei ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Tsetse Fly ◽  
Mammalian Host ◽  
African Trypanosomes ◽  
Protein Tyrosine ◽  
Ptp1b Inhibitors ◽  
Stumpy Form

Differentiation in African trypanosomes (Trypanosoma brucei) entails passage between a mammalian host, where parasites exist as a proliferative slender form or a G0-arrested stumpy form, and the tsetse fly. Stumpy forms arise at the peak of each parasitaemia and are committed to differentiation to procyclic forms that inhabit the tsetse midgut. We have identified a protein tyrosine phosphatase (TbPTP1) that inhibits trypanosome differentiation. Consistent with a tyrosine phosphatase, recombinant TbPTP1 exhibits the anticipated substrate and inhibitor profile, and its activity is impaired by reversible oxidation. TbPTP1 inactivation in monomorphic bloodstream trypanosomes by RNA interference or pharmacological inhibition triggers spontaneous differentiation to procyclic forms in a subset of committed cells. Consistent with this observation, homogeneous populations of stumpy forms synchronously differentiate to procyclic forms when tyrosine phosphatase activity is inhibited. Our data invoke a new model for trypanosome development in which differentiation to procyclic forms is prevented in the bloodstream by tyrosine dephosphorylation. It may be possible to use PTP1B inhibitors to block trypanosomatid transmission.

scholarly journals Dermal bacterial LPS-stimulation reduces susceptibility to intradermal Trypanosoma brucei infection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Omar A. Alfituri ◽  
Enock M. Mararo ◽  
Pieter C. Steketee ◽  
Liam J. Morrison ◽  
Neil A. Mabbott
Keyword(s):  
Trypanosoma Brucei ◽  
Early Stage ◽  
Lymphatic Vessels ◽  
Tsetse Fly ◽  
In Vitro Assays ◽  
African Trypanosomes ◽  
Host Protection ◽  
Dermal Injection ◽  
Gain Access

AbstractInfections with Trypanosoma brucei sp. are established after the injection of metacyclic trypomastigotes into the skin dermis by the tsetse fly vector. The parasites then gain access to the local lymphatic vessels to infect the local draining lymph nodes and disseminate systemically via the bloodstream. Macrophages are considered to play an important role in host protection during the early stage of systemic trypanosome infections. Macrophages are abundant in the skin dermis, but relatively little is known of their impact on susceptibility to intradermal (ID) trypanosome infections. We show that although dermal injection of colony stimulating factor 1 (CSF1) increased the local abundance of macrophages in the skin, this did not affect susceptibility to ID T. brucei infection. However, bacterial LPS-stimulation in the dermis prior to ID trypanosome infection significantly reduced disease susceptibility. In vitro assays showed that LPS-stimulated macrophage-like RAW264.7 cells had enhanced cytotoxicity towards T. brucei, implying that dermal LPS-treatment may similarly enhance the ability of dermal macrophages to eliminate ID injected T. brucei parasites in the skin. A thorough understanding of the factors that reduce susceptibility to ID injected T. brucei infections may lead to the development of novel strategies to help reduce the transmission of African trypanosomes.

scholarly journals Gene Co-Expression Network Analysis of Trypanosoma brucei in Tsetse Fly Vector

2020 ◽  
Author(s):  
Kennedy W. Mwangi ◽  
Rosaline W. Macharia ◽  
Joel L. Bargul
Keyword(s):  
Trypanosoma Brucei ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Protein Biosynthesis ◽  
Regulatory Elements ◽  
Tsetse Fly ◽  
Sub Saharan Africa ◽  
Mammalian Host ◽  
African Trypanosomes ◽  
Gene Modules

Abstract BackgroundTrypanosoma brucei species are motile protozoan parasites that are cyclically transmitted by tsetse fly (genus Glossina) causing human sleeping sickness and nagana in livestock in sub-Saharan Africa. African trypanosomes display digenetic life cycle stages in the tsetse fly vector and in their mammalian host. Experimental work on insect-stage trypanosomes is challenging due to the difficulty in setting up successful in vitro cultures. Therefore, there is limited knowledge on the trypanosome biology during its development in the tsetse fly. Consequently, this limits the development of new strategies for blocking parasite transmission in the tsetse fly. MethodsIn this study, RNA-Seq data of insect-stage trypanosomes were used to construct a T. brucei gene co-expression network using weighted gene co-expression analysis (WGCNA) method. The study identified significant enriched modules for genes that play key roles during the parasite’s development in tsetse fly. Further, potential 3’ untranslated region (UTR) regulatory elements for genes that clustered in the same module were identified using Finding Informative Regulatory Elements (FIRE) tool.ResultsA fraction of gene modules (12 out of 27 modules) in the constructed network were found to be enriched in functional roles associated with cell division, protein biosynthesis, mitochondrion, and cell surface. Additionally, 12 hub genes encoding proteins such as RNA-binding protein 6 (RBP6), Arginine kinase 1 (AK1), brucei alanine rich protein (BARP), among others, were identified for the 12 significantly enriched gene modules. In addition, the potential regulatory elements located in the 3’ untranslated regions of genes within the same module were predicted. ConclusionsThe constructed gene co-expression network provides a useful resource for network-based data mining to identify candidate genes for functional studies. This will enhance understanding of the molecular mechanisms that underlie important biological processes during parasite’s development in tsetse fly. Ultimately, these findings will be key in the identification of potential molecular targets for disease control.

scholarly journals Positional Dynamics and Glycosomal Recruitment of Developmental Regulators during Trypanosome Differentiation

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Balázs Szöőr ◽  
Dorina V. Simon ◽  
Federico Rojas ◽  
Julie Young ◽  
Derrick R. Robinson ◽  
...  
Keyword(s):  
Life Cycle ◽  
Trypanosoma Brucei ◽  
Tyrosine Phosphatase ◽  
Tsetse Fly ◽  
Sub Saharan Africa ◽  
Metabolic Adaptation ◽  
Tsetse Flies ◽  
Content Type ◽  
African Trypanosomes ◽  
Sub Saharan

ABSTRACT Glycosomes are peroxisome-related organelles that compartmentalize the glycolytic enzymes in kinetoplastid parasites. These organelles are developmentally regulated in their number and composition, allowing metabolic adaptation to the parasite’s needs in the blood of mammalian hosts or within their arthropod vector. A protein phosphatase cascade regulates differentiation between parasite developmental forms, comprising a tyrosine phosphatase, Trypanosoma brucei PTP1 (TbPTP1), which dephosphorylates and inhibits a serine threonine phosphatase, TbPIP39, which promotes differentiation. When TbPTP1 is inactivated, TbPIP39 is activated and during differentiation becomes located in glycosomes. Here we have tracked TbPIP39 recruitment to glycosomes during differentiation from bloodstream “stumpy” forms to procyclic forms. Detailed microscopy and live-cell imaging during the synchronous transition between life cycle stages revealed that in stumpy forms, TbPIP39 is located at a periflagellar pocket site closely associated with TbVAP, which defines the flagellar pocket endoplasmic reticulum. TbPTP1 is also located at the same site in stumpy forms, as is REG9.1, a regulator of stumpy-enriched mRNAs. This site provides a molecular node for the interaction between TbPTP1 and TbPIP39. Within 30 min of the initiation of differentiation, TbPIP39 relocates to glycosomes, whereas TbPTP1 disperses to the cytosol. Overall, the study identifies a “stumpy regulatory nexus” (STuRN) that coordinates the molecular components of life cycle signaling and glycosomal development during transmission of Trypanosoma brucei. IMPORTANCE African trypanosomes are parasites of sub-Saharan Africa responsible for both human and animal disease. The parasites are transmitted by tsetse flies, and completion of their life cycle involves progression through several development steps. The initiation of differentiation between blood and tsetse fly forms is signaled by a phosphatase cascade, ultimately trafficked into peroxisome-related organelles called glycosomes that are unique to this group of organisms. Glycosomes undergo substantial remodeling of their composition and function during the differentiation step, but how this is regulated is not understood. Here we identify a cytological site where the signaling molecules controlling differentiation converge before the dispersal of one of them into glycosomes. In combination, the study provides the first insight into the spatial coordination of signaling pathway components in trypanosomes as they undergo cell-type differentiation.

scholarly journals A Mitogen-Activated Protein Kinase Controls Differentiation of Bloodstream Forms of Trypanosoma brucei

2006 ◽  
Vol 5 (7) ◽  
pp. 1126-1135 ◽  
Author(s):  
Debora Domenicali Pfister ◽  
Gabriela Burkard ◽  
Sabine Morand ◽  
Christina Kunz Renggli ◽  
Isabel Roditi ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Tsetse Fly ◽  
Mitogen Activated Protein Kinase ◽  
Regulatory Function ◽  
Mammalian Host ◽  
Mutant Form ◽  
Wild Type ◽  
African Trypanosomes ◽  
Life Cycle Stages ◽  
Mitogen Activated Protein

ABSTRACT African trypanosomes undergo differentiation in order to adapt to the mammalian host and the tsetse fly vector. To characterize the role of a mitogen-activated protein (MAP) kinase homologue, TbMAPK5, in the differentiation of Trypanosoma brucei, we constructed a knockout in procyclic (insect) forms from a differentiation-competent (pleomorphic) stock. Two independent knockout clones proliferated normally in culture and were not essential for other life cycle stages in the fly. They were also able to infect immunosuppressed mice, but the peak parasitemia was 16-fold lower than that of the wild type. Differentiation of the proliferating long slender to the nonproliferating short stumpy bloodstream form is triggered by an autocrine factor, stumpy induction factor (SIF). The knockout differentiated prematurely in mice and in culture, suggestive of increased sensitivity to SIF. In contrast, a null mutant of a cell line refractory to SIF was able to proliferate normally. The differentiation phenotype was partially rescued by complementation with wild-type TbMAPK5 but exacerbated by introduction of a nonactivatable mutant form. Our results indicate a regulatory function for TbMAPK5 in the differentiation of bloodstream forms of T. brucei that might be exploitable as a target for chemotherapy against human sleeping sickness.

scholarly journals Depletion of the thioredoxin homologue tryparedoxin impairs antioxidative defence in African trypanosomes

2007 ◽  
Vol 402 (1) ◽  
pp. 43-49 ◽  
Author(s):  
Marcelo A. Comini ◽  
R. Luise Krauth-Siegel ◽  
Leopold Flohé
Keyword(s):  
Oxidative Stress ◽  
Rna Interference ◽  
Trypanosoma Brucei ◽  
Growth Phase ◽  
Essential Role ◽  
Biological Significance ◽  
Tsetse Fly ◽  
African Trypanosomes ◽  
Antioxidative Defence

In trypanosomes, the thioredoxin-type protein TXN (tryparedoxin) is a multi-purpose oxidoreductase that is involved in the detoxification of hydroperoxides, the synthesis of DNA precursors and the replication of the kinetoplastid DNA. African trypanosomes possess two isoforms that are localized in the cytosol and in the mitochondrion of the parasites respectively. Here we report on the biological significance of the cTXN (cytosolic TXN) of Trypanosoma brucei for hydroperoxide detoxification. Depending on the growth phase, the concentration of the protein is 3–7-fold higher in the parasite form infecting mammals (50–100 μM) than in the form hosted by the tsetse fly (7–34 μM). Depletion of the mRNA in bloodstream trypanosomes by RNA interference revealed the indispensability of the protein. Proliferation and viability of cultured trypanosomes were impaired when TXN was lowered to 1 μM for more than 48 h. Although the levels of glutathione, glutathionylspermidine and trypanothione were increased 2–3.5-fold, the sensitivity against exogenously generated H2O2 was significantly enhanced. The results prove the essential role of the cTXN and its pivotal function in the parasite defence against oxidative stress.

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