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11 pages, 8727 KiB

Open AccessEditor’s ChoiceArticle

Acidocalcisome-Mitochondrion Membrane Contact Sites in Trypanosoma brucei

by Srinivasan Ramakrishnan, Beejan Asady and Roberto Docampo

Pathogens 2018, 7(2), 33; https://doi.org/10.3390/pathogens7020033 - 22 Mar 2018

Cited by 26 | Viewed by 5431

Membrane contact sites are regions of close apposition between two organelles, typically less than 30 nanometers apart, that facilitate transfer of biomolecules. The presence of contact sites has been demonstrated in yeast, plants, and mammalian cells. Here, we investigated the presence of such [...] Read more.

Membrane contact sites are regions of close apposition between two organelles, typically less than 30 nanometers apart, that facilitate transfer of biomolecules. The presence of contact sites has been demonstrated in yeast, plants, and mammalian cells. Here, we investigated the presence of such contact sites in Trypanosoma brucei. In mammalian cells, endoplasmic reticulum-mitochondria contact sites facilitate mitochondrial uptake of Ca²⁺ released by the ER-located inositol 1,4,5-trisphosphate receptor (InsP₃R). However, the InsP₃R in trypanosomes localizes to acidocalcisomes, which serve as major Ca²⁺ stores in these parasites. In this work, we have used super-resolution structured illumination microscopy and electron microscopy to identify membrane contact sites that exist between acidocalcisomes and mitochondria. Furthermore, we have confirmed the close association of these organelles using proximity ligation assays. Characterization of these contact sites may be a necessary starting point towards unraveling the role of Ca²⁺ in regulating trypanosome bioenergetics. Full article

(This article belongs to the Special Issue Trypanosoma brucei)

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754 KiB

Open AccessArticle

The Lipid Raft Proteome of African Trypanosomes Contains Many Flagellar Proteins

by Aabha I. Sharma, Cheryl L. Olson and David M. Engman

Pathogens 2017, 6(3), 39; https://doi.org/10.3390/pathogens6030039 - 24 Aug 2017

Cited by 7 | Viewed by 4621

Abstract

Lipid rafts are liquid-ordered membrane microdomains that form by preferential association of 3-β-hydroxysterols, sphingolipids and raft-associated proteins often having acyl modifications. We isolated lipid rafts of the protozoan parasite Trypanosoma brucei and determined the protein composition of lipid rafts in the cell. This [...] Read more.

Lipid rafts are liquid-ordered membrane microdomains that form by preferential association of 3-β-hydroxysterols, sphingolipids and raft-associated proteins often having acyl modifications. We isolated lipid rafts of the protozoan parasite Trypanosoma brucei and determined the protein composition of lipid rafts in the cell. This analysis revealed a striking enrichment of flagellar proteins and several putative signaling proteins in the lipid raft proteome. Calpains and intraflagellar transport proteins, in particular, were found to be abundant in the lipid raft proteome. These findings provide additional evidence supporting the notion that the eukaryotic cilium/flagellum is a lipid raft-enriched specialized structure with high concentrations of sterols, sphingolipids and palmitoylated proteins involved in environmental sensing and cell signaling. Full article

(This article belongs to the Special Issue Trypanosoma brucei)

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5964 KiB

Open AccessArticle

ProtozoaDB 2.0: A Trypanosoma Brucei Case Study

by Rodrigo Jardim, Diogo Tschoeke and Alberto M. R. Dávila

Pathogens 2017, 6(3), 32; https://doi.org/10.3390/pathogens6030032 - 20 Jul 2017

Cited by 1 | Viewed by 3719

Abstract

Over the last decade new species of Protozoa have been sequenced and deposited in GenBank. Analyzing large amounts of genomic data, especially using Next Generation Sequencing (NGS), is not a trivial task, considering that researchers used to deal or focus their studies on [...] Read more.

Over the last decade new species of Protozoa have been sequenced and deposited in GenBank. Analyzing large amounts of genomic data, especially using Next Generation Sequencing (NGS), is not a trivial task, considering that researchers used to deal or focus their studies on few genes or gene families or even small genomes. To facilitate the information extraction process from genomic data, we developed a database system called ProtozoaDB that included five genomes of Protozoa in its first version. In the present study, we present a new version of ProtozoaDB called ProtozoaDB 2.0, now with the genomes of 22 pathogenic Protozoa. The system has been fully remodeled to allow for new tools and a more expanded view of data, and now includes a number of analyses such as: (i) similarities with other databases (model organisms, the Conserved Domains Database, and the Protein Data Bank); (ii) visualization of KEGG metabolic pathways; (iii) the protein structure from PDB; (iv) homology inferences; (v) the search for related publications in PubMed; (vi) superfamily classification; and (vii) phenotype inferences based on comparisons with model organisms. ProtozoaDB 2.0 supports RESTful Web Services to make data access easier. Those services were written in Ruby language using Ruby on Rails (RoR). This new version also allows a more detailed analysis of the object of study, as well as expanding the number of genomes and proteomes available to the scientific community. In our case study, a group of prenyltransferase proteinsalready described in the literature was found to be a good drug target for Trypanosomatids. Full article

(This article belongs to the Special Issue Trypanosoma brucei)

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Review

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19 pages, 564 KiB

Open AccessReview

Separating the Wheat from the Chaff: RNA Editing and Selection of Translatable mRNA in Trypanosome Mitochondria

by Dmitri A. Maslov

Pathogens 2019, 8(3), 105; https://doi.org/10.3390/pathogens8030105 - 18 Jul 2019

Cited by 4 | Viewed by 3448

Abstract

In the mitochondria of trypanosomes and related kinetoplastid protists, most mRNAs undergo a long and sophisticated maturation pathway before they can be productively translated by mitochondrial ribosomes. Some of the aspects of this pathway (identity of the promotors, transcription initiation, and termination signals) [...] Read more.

In the mitochondria of trypanosomes and related kinetoplastid protists, most mRNAs undergo a long and sophisticated maturation pathway before they can be productively translated by mitochondrial ribosomes. Some of the aspects of this pathway (identity of the promotors, transcription initiation, and termination signals) remain obscure, and some (post-transcriptional modification by U-insertion/deletion, RNA editing, 3′-end maturation) have been illuminated by research during the last decades. The RNA editing creates an open reading frame for a productive translation, but the fully edited mRNA often represents a minor fraction in the pool of pre-edited and partially edited precursors. Therefore, it has been expected that the final stages of the mRNA processing generate molecular hallmarks, which allow for the efficient and selective recognition of translation-competent templates. The general contours and several important details of this process have become known only recently and represent the subject of this review. Full article

(This article belongs to the Special Issue Trypanosoma brucei)

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22 pages, 2383 KiB

Open AccessFeature PaperReview

Adenylate Cyclases of Trypanosoma brucei, Environmental Sensors and Controllers of Host Innate Immune Response

by Didier Salmon

Pathogens 2018, 7(2), 48; https://doi.org/10.3390/pathogens7020048 - 25 Apr 2018

Cited by 14 | Viewed by 10580

Abstract

Trypanosoma brucei, etiological agent of Sleeping Sickness in Africa, is the prototype of African trypanosomes, protozoan extracellular flagellate parasites transmitted by saliva (Salivaria). In these parasites the molecular controls of the cell cycle and environmental sensing are elaborate and concentrated [...] Read more.

Trypanosoma brucei, etiological agent of Sleeping Sickness in Africa, is the prototype of African trypanosomes, protozoan extracellular flagellate parasites transmitted by saliva (Salivaria). In these parasites the molecular controls of the cell cycle and environmental sensing are elaborate and concentrated at the flagellum. Genomic analyses suggest that these parasites appear to differ considerably from the host in signaling mechanisms, with the exception of receptor-type adenylate cyclases (AC) that are topologically similar to receptor-type guanylate cyclase (GC) of higher eukaryotes but control a new class of cAMP targets of unknown function, the cAMP response proteins (CARPs), rather than the classical protein kinase A cAMP effector (PKA). T. brucei possesses a large polymorphic family of ACs, mainly associated with the flagellar membrane, and these are involved in inhibition of the innate immune response of the host prior to the massive release of immunomodulatory factors at the first peak of parasitemia. Recent evidence suggests that in T. brucei several insect-specific AC isoforms are involved in social motility, whereas only a few AC isoforms are involved in cytokinesis control of bloodstream forms, attesting that a complex signaling pathway is required for environmental sensing. In this review, after a general update on cAMP signaling pathway and the multiple roles of cAMP, I summarize the existing knowledge of the mechanisms by which pathogenic microorganisms modulate cAMP levels to escape immune defense. Full article

(This article belongs to the Special Issue Trypanosoma brucei)

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45 pages, 2111 KiB

Open AccessEditor’s ChoiceReview

The Uptake and Metabolism of Amino Acids, and Their Unique Role in the Biology of Pathogenic Trypanosomatids

by Letícia Marchese, Janaina De Freitas Nascimento, Flávia Silva Damasceno, Frédéric Bringaud, Paul A. M. Michels and Ariel Mariano Silber

Pathogens 2018, 7(2), 36; https://doi.org/10.3390/pathogens7020036 - 01 Apr 2018

Cited by 56 | Viewed by 12699

Abstract

Trypanosoma brucei, as well as Trypanosoma cruzi and more than 20 species of the genus Leishmania, form a group of flagellated protists that threaten human health. These organisms are transmitted by insects that, together with mammals, are their natural hosts. This [...] Read more.

Trypanosoma brucei, as well as Trypanosoma cruzi and more than 20 species of the genus Leishmania, form a group of flagellated protists that threaten human health. These organisms are transmitted by insects that, together with mammals, are their natural hosts. This implies that during their life cycles each of them faces environments with different physical, chemical, biochemical, and biological characteristics. In this work we review how amino acids are obtained from such environments, how they are metabolized, and how they and some of their intermediate metabolites are used as a survival toolbox to cope with the different conditions in which these parasites should establish the infections in the insects and mammalian hosts. Full article

(This article belongs to the Special Issue Trypanosoma brucei)

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1969 KiB

Open AccessFeature PaperReview

The Role of Cytoplasmic mRNA Cap-Binding Protein Complexes in Trypanosoma brucei and Other Trypanosomatids

by Eden R. Freire, Nancy R. Sturm, David A. Campbell and Osvaldo P. De Melo Neto

Pathogens 2017, 6(4), 55; https://doi.org/10.3390/pathogens6040055 - 27 Oct 2017

Cited by 45 | Viewed by 7472

Abstract

Trypanosomatid protozoa are unusual eukaryotes that are well known for having unusual ways of controlling their gene expression. The lack of a refined mode of transcriptional control in these organisms is compensated by several post-transcriptional control mechanisms, such as control of mRNA turnover [...] Read more.

Trypanosomatid protozoa are unusual eukaryotes that are well known for having unusual ways of controlling their gene expression. The lack of a refined mode of transcriptional control in these organisms is compensated by several post-transcriptional control mechanisms, such as control of mRNA turnover and selection of mRNA for translation, that may modulate protein synthesis in response to several environmental conditions found in different hosts. In other eukaryotes, selection of mRNA for translation is mediated by the complex eIF4F, a heterotrimeric protein complex composed by the subunits eIF4E, eIF4G, and eIF4A, where the eIF4E binds to the 5′-cap structure of mature mRNAs. In this review, we present and discuss the characteristics of six trypanosomatid eIF4E homologs and their associated proteins that form multiple eIF4F complexes. The existence of multiple eIF4F complexes in trypanosomatids evokes exquisite mechanisms for differential mRNA recognition for translation. Full article

(This article belongs to the Special Issue Trypanosoma brucei)

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4081 KiB

Open AccessFeature PaperReview

Microfluidics-Based Approaches to the Isolation of African Trypanosomes

by Michael P. Barrett, Jonathan M. Cooper, Clément Regnault, Stefan H. Holm, Jason P. Beech, Jonas O. Tegenfeldt and Axel Hochstetter

Pathogens 2017, 6(4), 47; https://doi.org/10.3390/pathogens6040047 - 05 Oct 2017

Cited by 7 | Viewed by 6536

Abstract

African trypanosomes are responsible for significant levels of disease in both humans and animals. The protozoan parasites are free-living flagellates, usually transmitted by arthropod vectors, including the tsetse fly. In the mammalian host they live in the bloodstream and, in the case of [...] Read more.

African trypanosomes are responsible for significant levels of disease in both humans and animals. The protozoan parasites are free-living flagellates, usually transmitted by arthropod vectors, including the tsetse fly. In the mammalian host they live in the bloodstream and, in the case of human-infectious species, later invade the central nervous system. Diagnosis of the disease requires the positive identification of parasites in the bloodstream. This can be particularly challenging where parasite numbers are low, as is often the case in peripheral blood. Enriching parasites from body fluids is an important part of the diagnostic pathway. As more is learned about the physicochemical properties of trypanosomes, this information can be exploited through use of different microfluidic-based approaches to isolate the parasites from blood or other fluids. Here, we discuss recent advances in the use of microfluidics to separate trypanosomes from blood and to isolate single trypanosomes for analyses including drug screening. Full article

(This article belongs to the Special Issue Trypanosoma brucei)

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1168 KiB

Open AccessReview

The Cytological Events and Molecular Control of Life Cycle Development of Trypanosoma brucei in the Mammalian Bloodstream

by Eleanor Silvester, Kirsty R. McWilliam and Keith R. Matthews

Pathogens 2017, 6(3), 29; https://doi.org/10.3390/pathogens6030029 - 28 Jun 2017

Cited by 43 | Viewed by 19050

Abstract

African trypanosomes cause devastating disease in sub-Saharan Africa in humans and livestock. The parasite lives extracellularly within the bloodstream of mammalian hosts and is transmitted by blood-feeding tsetse flies. In the blood, trypanosomes exhibit two developmental forms: the slender form and the stumpy [...] Read more.

African trypanosomes cause devastating disease in sub-Saharan Africa in humans and livestock. The parasite lives extracellularly within the bloodstream of mammalian hosts and is transmitted by blood-feeding tsetse flies. In the blood, trypanosomes exhibit two developmental forms: the slender form and the stumpy form. The slender form proliferates in the bloodstream, establishes the parasite numbers and avoids host immunity through antigenic variation. The stumpy form, in contrast, is non-proliferative and is adapted for transmission. Here, we overview the features of slender and stumpy form parasites in terms of their cytological and molecular characteristics and discuss how these contribute to their distinct biological functions. Thereafter, we describe the technical developments that have enabled recent discoveries that uncover how the slender to stumpy transition is enacted in molecular terms. Finally, we highlight new understanding of how control of the balance between slender and stumpy form parasites interfaces with other components of the infection dynamic of trypanosomes in their mammalian hosts. This interplay between the host environment and the parasite’s developmental biology may expose new vulnerabilities to therapeutic attack or reveal where drug control may be thwarted by the biological complexity of the parasite’s lifestyle. Full article

(This article belongs to the Special Issue Trypanosoma brucei)

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