scholarly journals Glucose Signaling Is Important for Nutrient Adaptation during Differentiation of Pleomorphic African Trypanosomes

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Yijian Qiu ◽  
Jillian E. Milanes ◽  
Jessica A. Jones ◽  
Rooksana E. Noorai ◽  
Vijay Shankar ◽  
...  
Keyword(s):  
Life Cycle ◽  
Glucose Sensing ◽  
Negative Regulator ◽  
Bloodstream Form ◽  
Tsetse Flies ◽  
Insect Vector ◽  
Rapid Reduction ◽  
African Trypanosomes ◽  
Procyclic Form ◽  
African Trypanosome

ABSTRACT The African trypanosome has evolved mechanisms to adapt to changes in nutrient availability that occur during its life cycle. During transition from mammalian blood to insect vector gut, parasites experience a rapid reduction in environmental glucose. Here we describe how pleomorphic parasites respond to glucose depletion with a focus on parasite changes in energy metabolism and growth. Long slender bloodstream form parasites were rapidly killed as glucose concentrations fell, while short stumpy bloodstream form parasites persisted to differentiate into the insect-stage procyclic form parasite. The rate of differentiation was lower than that triggered by other cues but reached physiological rates when combined with cold shock. Both differentiation and growth of resulting procyclic form parasites were inhibited by glucose and nonmetabolizable glucose analogs, and these parasites were found to have upregulated amino acid metabolic pathway component gene expression. In summary, glucose transitions from the primary metabolite of the blood-stage infection to a negative regulator of cell development and growth in the insect vector, suggesting that the hexose is not only a key metabolic agent but also an important signaling molecule. IMPORTANCE As the African trypanosome Trypanosoma brucei completes its life cycle, it encounters many different environments. Adaptation to these environments includes modulation of metabolic pathways to parallel the availability of nutrients. Here, we describe how the blood-dwelling life cycle stages of the African trypanosome, which consume glucose to meet their nutritional needs, respond differently to culture in the near absence of glucose. The proliferative long slender parasites rapidly die, while the nondividing short stumpy parasite remains viable and undergoes differentiation to the next life cycle stage, the procyclic form parasite. Interestingly, a sugar analog that cannot be used as an energy source inhibited the process. Furthermore, the growth of procyclic form parasite that resulted from the event was inhibited by glucose, a behavior that is similar to that of parasites isolated from tsetse flies. Our findings suggest that glucose sensing serves as an important modulator of nutrient adaptation in the parasite.

scholarly journals Glucose signaling is important for nutrient adaptation during differentiation of pleomorphic African trypanosomes

2018 ◽  
Author(s):  
Yijian Qiu ◽  
Jillian E. Milanes ◽  
Jessica A. Jones ◽  
Rooksana E. Noorai ◽  
Vijay Shankar ◽  
...  
Keyword(s):  
Glucose Sensing ◽  
Negative Regulator ◽  
Bloodstream Form ◽  
Tsetse Flies ◽  
Insect Vector ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
African Trypanosomes ◽  
Procyclic Form ◽  
African Trypanosome

AbstractThe African trypanosome has evolved mechanisms to adapt to changes in nutrient availability that occur during its lifecycle. During transition from mammalian blood to insect vector gut, parasites experience a rapid reduction in environmental glucose. Here we describe how pleomorphic parasites respond to glucose depletion with a focus on parasite changes in energy metabolism and growth. Long slender bloodstream form parasites are rapidly killed as glucose concentrations fall, while the short stumpy bloodstream form parasites persist to differentiate into the insect stage procyclic form parasite. The rate of differentiation was slower than that triggered by other cues but reached physiological rates when combined with cold shock. Both differentiation and growth of resulting procyclic form parasites were inhibited by glucose and its non-metabolizable analogs in a concentration dependent manner. Procyclic form parasites differentiated from short stumpy form parasites in glucose depleted medium significantly upregulated gene expression of amino acid metabolic pathway components when compared to procyclic forms generated by cis-aconitate treatment. Additionally, growth of these parasite was inhibited by the presence of either glucose or 6-deoxyglucose. In summary, glucose transitions from the primary metabolite of the blood stage infection to a negative regulator of cell development and growth in the insect vector, suggesting that the hexose is not only a key metabolic agent but is also an important signaling molecule.Author SummaryAs the African trypanosome, Trypanosoma brucei, completes its lifecycle, it encounters many different environments. Adaptation to these environments includes modulation of metabolic pathways to parallel the availability of nutrients. Here, we describe how the blood-dwelling lifecycle stages of the African trypanosome, which consume glucose to meet their nutritional needs, respond differently to culture in the near absence of glucose. The proliferative long slender parasites rapidly die, while the non-dividing short stumpy remains viable and undergoes differentiation to the next lifecycle stage, the procyclic form parasite. Interestingly a sugar analog that cannot be used as an energy source inhibited the process. Furthermore, the growth of procyclic form parasite that resulted from the event was inhibited by glucose, a behavior that is similar to that of parasites isolated from tsetse flies. Our findings suggest that glucose sensing serves as an important modulator of nutrient adaptation in the parasite.

Mitochondrial genome repositioning during the differentiation of the African trypanosome between life cycle forms is microtubule mediated

1995 ◽  
Vol 108 (6) ◽  
pp. 2231-2239 ◽  
Author(s):  
K.R. Matthews ◽  
T. Sherwin ◽  
K. Gull
Keyword(s):  
Cell Cycle ◽  
Mitochondrial Dna ◽  
Life Cycle ◽  
Mitochondrial Genome ◽  
Complex Life Cycle ◽  
African Trypanosomes ◽  
Procyclic Form ◽  
African Trypanosome ◽  
Replication Phase ◽  
Dependent Processes

The cell cycle of the African trypanosome requires a precise orchestration of nuclear and mitochondrial genome (kinetoplast) positioning to ensure faithful segregation during division. The controls underlying these events must be subject to modulation, however, as the respective positioning of these organelles changes during the parasite's complex life cycle. We have studied mitochondrial DNA repositioning during differentiation between the trypanosome's bloodstream and procyclic form. We have found that repositioning occurs simultaneously with the DNA replication phase of the cell cycle of the differentiating parasite. Furthermore, we demonstrate, at the cell and individual microtubule level, that this organelle repositioning is achieved via microtubule-dependent processes. Our results have implications for the control of cell differentiation and division in African trypanosomes.

scholarly journals Functional Analyses of Cytokinesis Regulators in Bloodstream Stage Trypanosoma brucei Parasites Identify Functions and Regulations Specific to the Life Cycle Stage

mSphere ◽  
2019 ◽  
Vol 4 (3) ◽  
Author(s):  
Xuan Zhang ◽  
Tai An ◽  
Kieu T. M. Pham ◽  
Zhao-Rong Lun ◽  
Ziyin Li
Keyword(s):  
Life Cycle ◽  
Trypanosoma Brucei ◽  
Protozoan Parasite ◽  
Bloodstream Form ◽  
Signaling Cascade ◽  
Insect Vector ◽  
Content Type ◽  
Procyclic Form ◽  
Life Cycle Stages ◽  
Evolutionarily Conserved

ABSTRACT The early divergent protozoan parasite Trypanosoma brucei alternates between the insect vector and the mammalian hosts during its life cycle and proliferates through binary cell fission. The cell cycle control system in T. brucei differs substantially from that in its mammalian hosts and possesses distinct mitosis-cytokinesis checkpoint controls between two life cycle stages, the procyclic form and the bloodstream form. T. brucei undergoes an unusual mode of cytokinesis, which is controlled by a novel signaling cascade consisting of evolutionarily conserved protein kinases and trypanosome-specific regulatory proteins in the procyclic form. However, given the distinct mitosis-cytokinesis checkpoints between the two forms, it is unclear whether the cytokinesis regulatory pathway discovered in the procyclic form also operates in a similar manner in the bloodstream form. Here, we showed that the three regulators of cytokinesis initiation, cytokinesis initiation factor 1 (CIF1), CIF2, and CIF3, are interdependent for subcellular localization but not for protein stability as in the procyclic form. Further, we demonstrated that KLIF, a regulator of cytokinesis completion in the procyclic form, plays limited roles in cytokinesis in the bloodstream form. Finally, we showed that the cleavage furrow-localizing protein FRW1 is required for cytokinesis initiation in the bloodstream form but is nonessential for cytokinesis in the procyclic form. Together, these results identify conserved and life cycle-specific functions of cytokinesis regulators, highlighting the distinction in the regulation of cytokinesis between different life cycle stages of T. brucei. IMPORTANCE The early divergent protozoan parasite Trypanosoma brucei is the causative agent of sleeping sickness in humans and nagana in cattle in sub-Saharan Africa. This parasite has a complex life cycle by alternating between the insect vector and the mammalian hosts and proliferates by binary cell fission. The control of cell division in trypanosomes appears to be distinct from that in its human host and differs substantially between two life cycle stages, the procyclic (insect) form and the bloodstream form. Cytokinesis, the final step of binary cell fission, is regulated by a novel signaling cascade consisting of two evolutionarily conserved protein kinases and a cohort of trypanosome-specific regulators in the procyclic form, but whether this signaling pathway operates in a similar manner in the bloodstream form is unclear. In this report, we performed a functional analysis of multiple cytokinesis regulators and discovered their distinct functions and regulations in the bloodstream form.

scholarly journals Novel Observations Concerning Differentiation of Bloodstream-Form Trypanosomes to the Form That Is Adapted for Growth in Tsetse Flies

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Christine Clayton
Keyword(s):  
Cold Shock ◽  
Tricarboxylic Acid ◽  
Bloodstream Form ◽  
Tsetse Flies ◽  
Data Sets ◽  
Glucose Medium ◽  
Transcriptome Data ◽  
Procyclic Form ◽  
Link Type ◽  
Highly Efficient

ABSTRACT Salivarian trypanosomes grow in mammals, where they depend on glucose, and as procyclic forms in tsetse flies, where they metabolize proline. Differentiation of bloodstream forms to nongrowing stumpy forms, and to procyclic forms, has been studied extensively, but reconciling the results is tricky because investigators have used parasites with various differentiation competences and different media for procyclic-form culture. Standard protocols include lowering the temperature to 27°C, adding a tricarboxylic acid, and transferring the parasites to high-proline medium, often including glucose. A 20°C cold shock enhanced efficiency. Y. Qiu, J. E. Milanes, J. A. Jones, R. E. Noorai, et al. (mSphere 3:e00366-18, 2018, https://doi.org/10.1128/mSphere.00366-18) studied this systematically, and their results call long-established protocols into question. Importantly, highly efficient differentiation was observed after cold shock and transfer to no-glucose medium without tricarboxylic acid; in contrast, glucose made differentiation tricarboxylic acid dependent and inhibited procyclic growth. New transcriptome data for stumpy and procyclic forms will enable informative comparisons with biochemical observations and with other RNA and protein data sets.

scholarly journals Mutualist-Provisioned Resources Impact Vector Competency

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Rita V. M. Rio ◽  
Anna K. S. Jozwick ◽  
Amy F. Savage ◽  
Afsoon Sabet ◽  
Aurelien Vigneron ◽  
...  
Keyword(s):  
Life Cycle ◽  
Disease Transmission ◽  
Tsetse Fly ◽  
Parasite Development ◽  
Vitamin B ◽  
Insect Vector ◽  
Trypanosome Infection ◽  
Content Type ◽  
African Trypanosomes ◽  
Vector Competency

ABSTRACT Many symbionts supplement their host’s diet with essential nutrients. However, whether these nutrients also enhance parasitism is unknown. In this study, we investigated whether folate (vitamin B9) production by the tsetse fly (Glossina spp.) essential mutualist, Wigglesworthia, aids auxotrophic African trypanosomes in completing their life cycle within this obligate vector. We show that the expression of Wigglesworthia folate biosynthesis genes changes with the progression of trypanosome infection within tsetse. The disruption of Wigglesworthia folate production caused a reduction in the percentage of flies that housed midgut (MG) trypanosome infections. However, decreased folate did not prevent MG trypanosomes from migrating to and establishing an infection in the fly’s salivary glands, thus suggesting that nutrient requirements vary throughout the trypanosome life cycle. We further substantiated that trypanosomes rely on symbiont-generated folate by feeding this vitamin to Glossina brevipalpis, which exhibits low trypanosome vector competency and houses Wigglesworthia incapable of producing folate. Folate-supplemented G. brevipalpis flies were significantly more susceptible to trypanosome infection, further demonstrating that this vitamin facilitates parasite infection establishment. Our cumulative results provide evidence that Wigglesworthia provides a key metabolite (folate) that is “hijacked” by trypanosomes to enhance their infectivity, thus indirectly impacting tsetse species vector competency. Parasite dependence on symbiont-derived micronutrients, which likely also occurs in other arthropod vectors, represents a relationship that may be exploited to reduce disease transmission. IMPORTANCE Parasites elicit several physiological changes in their host to enhance transmission. Little is known about the functional association between parasitism and microbiota-provisioned resources typically dedicated to animal hosts and how these goods may be rerouted to optimize parasite development. This study is the first to identify a specific symbiont-generated metabolite that impacts insect vector competence by facilitating parasite establishment and, thus, eventual transmission. Specifically, we demonstrate that the tsetse fly obligate mutualist Wigglesworthia provisions folate (vitamin B9) that pathogenic African trypanosomes exploit in an effort to successfully establish an infection in the vector’s MG. This process is essential for the parasite to complete its life cycle and be transmitted to a new vertebrate host. Disrupting metabolic contributions provided by the microbiota of arthropod disease vectors may fuel future innovative control strategies while also offering minimal nontarget effects.

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 Mammalian African trypanosome VSG coat enhances tsetse’s vector competence

2016 ◽  
Vol 113 (25) ◽  
pp. 6961-6966 ◽  
Author(s):  
Emre Aksoy ◽  
Aurélien Vigneron ◽  
XiaoLi Bing ◽  
Xin Zhao ◽  
Michelle O’Neill ◽  
...  
Keyword(s):  
Disease Transmission ◽  
Vector Competence ◽  
Wnt Signaling Pathway ◽  
Sub Saharan Africa ◽  
Parasite Development ◽  
Mammalian Host ◽  
Tsetse Flies ◽  
Insect Vector ◽  
Coat Proteins ◽  
African Trypanosomes

Tsetse flies are biological vectors of African trypanosomes, the protozoan parasites responsible for causing human and animal trypanosomiases across sub-Saharan Africa. Currently, no vaccines are available for disease prevention due to antigenic variation of the Variant Surface Glycoproteins (VSG) that coat parasites while they reside within mammalian hosts. As a result, interference with parasite development in the tsetse vector is being explored to reduce disease transmission. A major bottleneck to infection occurs as parasites attempt to colonize tsetse’s midgut. One critical factor influencing this bottleneck is the fly’s peritrophic matrix (PM), a semipermeable, chitinous barrier that lines the midgut. The mechanisms that enable trypanosomes to cross this barrier are currently unknown. Here, we determined that as parasites enter the tsetse’s gut, VSG molecules released from trypanosomes are internalized by cells of the cardia—the tissue responsible for producing the PM. VSG internalization results in decreased expression of a tsetse microRNA (mir-275) and interferes with the Wnt-signaling pathway and the Iroquois/IRX transcription factor family. This interference reduces the function of the PM barrier and promotes parasite colonization of the gut early in the infection process. Manipulation of the insect midgut homeostasis by the mammalian parasite coat proteins is a novel function and indicates that VSG serves a dual role in trypanosome biology—that of facilitating transmission through its mammalian host and insect vector. We detail critical steps in the course of trypanosome infection establishment that can serve as novel targets to reduce the tsetse’s vector competence and disease transmission.

scholarly journals Slippery customers: How African trypanosomes evade mammalian defences

2009 ◽  
Vol 31 (4) ◽  
pp. 8-11
Author(s):  
Mark Carrington
Keyword(s):  
Cell Biology ◽  
Sub Saharan Africa ◽  
Mammalian Host ◽  
Tsetse Flies ◽  
Insect Vector ◽  
African Trypanosomiasis ◽  
Long Distance ◽  
African Trypanosomes ◽  
Endemic Areas ◽  
Sub Saharan

African trypanosomes are excellent parasites and can maintain an infection of a large mammalian host for months or years. In endemic areas, Human African Trypanosomiasis, also called sleeping sickness, has been largely unaffected by the advent of modern medicine, and trypanosomiasis of domestic livestock is a major restraint on productivity in endemic areas and is arguably the major contributor to the institutionalized poverty in much of rural sub-Saharan Africa1,2. A simple way of visualizing the effect of the livestock disease is to compare maps showing the distribution of livestock (www.ilri.org/InfoServ/Webpub/Fulldocs/Mappoverty/index.htm) and tsetse flies, the insect vector (www.fao.org/ag/AGAinfo/programmes/en/paat/maps.html): the lack of overlap is remarkable. Tsetse flies are only present in sub-Saharan Africa, and this probably restricted the spread of African trypanosomiasis until historical times. Livestock infections are now present in much of South Asia and South America, a product of long distance trade and adaptation of the trypanosomes to mechanical transmission3. The majority of research is on Trypanosoma brucei as this includes the human infective subspecies. This article provides a description of progress in the understanding the molecular details of how the trypanosome interacts with the mammalian immune system and how these studies have extended beyond this to fundamental aspects of eukaryotic cell biology.

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 Distinct Roles of a Mitogen-Activated Protein Kinase in Cytokinesis between Different Life Cycle Forms of Trypanosoma brucei

2013 ◽  
Vol 13 (1) ◽  
pp. 110-118 ◽  
Author(s):  
Ying Wei ◽  
Ziyin Li
Keyword(s):  
Life Cycle ◽  
Protein Kinase ◽  
Map Kinase ◽  
Trypanosoma Brucei ◽  
Bloodstream Form ◽  
Mitogen Activated Protein Kinase ◽  
Content Type ◽  
Procyclic Form ◽  
Moderate Growth ◽  
Mitogen Activated Protein

ABSTRACT Mitogen-activated protein kinase (MAPK) modules are evolutionarily conserved signaling cascades that function in response to the environment and play crucial roles in intracellular signal transduction in eukaryotes. The involvement of a MAP kinase in regulating cytokinesis in yeast, animals, and plants has been reported, but the requirement for a MAP kinase for cytokinesis in the early-branching protozoa is not documented. Here, we show that a MAP kinase homolog (TbMAPK6) from Trypanosoma brucei plays distinct roles in cytokinesis in two life cycle forms of T. brucei . TbMAPK6 is distributed throughout the cytosol in the procyclic form but is localized in both the cytosol and the nucleus in the bloodstream form. RNA interference (RNAi) of TbMAPK6 results in moderate growth inhibition in the procyclic form but severe growth defects and rapid cell death in the bloodstream form. Moreover, TbMAPK6 appears to be implicated in furrow ingression and cytokinesis completion in the procyclic form but is essential for cytokinesis initiation in the bloodstream form. Despite the distinct defects in cytokinesis in the two forms, RNAi of TbMAPK6 also caused defective basal body duplication/segregation in a small cell population in both life cycle forms. Altogether, our results demonstrate the involvement of the TbMAPK6-mediated pathway in regulating cytokinesis in trypanosomes and suggest distinct roles of TbMAPK6 in cytokinesis between different life cycle stages of T. brucei .

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