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Godwin U Ebiloma, Evangelos Katsoulis, John O Igoli, Alexander I Gray, Harry P De Koning
Natural products have made remarkable contributions to drug discovery and therapy. In this work we exploited various biochemical approaches to investigate the mode of action of 16-α-hydroxy-cleroda-3,13 (14)-Z-dien-15,16-olide (HDK-20), which we recently isolated from Polyalthia longifolia, on Trypanosoma brucei bloodstream trypomastigotes. HDK20 at concentrations ≥ EC50 (0.4 μg/ml) was trypanocidal, with its effect irreversible after only a brief exposure time (<1 h). Fluorescence microscopic assessment of DNA configuration revealed severe cell cycle defects after 8 h of incubation with the compound, the equivalent of a single generation time...
March 15, 2018: Scientific Reports
Céline Ronin, David Mendes Costa, Joana Tavares, Joana Faria, Fabrice Ciesielski, Paola Ciapetti, Terry K Smith, Jane MacDougall, Anabela Cordeiro-da-Silva, Iain K Pemberton
The de novo crystal structure of the Leishmania infantum Silent Information Regulator 2 related protein 1 (LiSir2rp1) has been solved at 1.99Å in complex with an acetyl-lysine peptide substrate. The structure is broadly commensurate with Hst2/SIRT2 proteins of yeast and human origin, reproducing many of the structural features common to these sirtuin deacetylases, including the characteristic small zinc-binding domain, and the larger Rossmann-fold domain involved in NAD+-binding interactions. The two domains are linked via a cofactor binding loop ordered in open conformation...
2018: PloS One
Laura Jeacock, Joana Faria, David Horn
Protein abundance differs from a few to millions of copies per cell. Trypanosoma brucei presents an excellent model for studies on codon bias and differential gene expression because transcription is broadly unregulated and uniform across the genome. T. brucei is also a major human and animal protozoal pathogen. Here, an experimental assessment, using synthetic reporter genes, revealed that GC3 codons have a major positive impact on both mRNA and protein abundance. Our estimates of relative expression, based on coding sequences alone (codon usage and sequence length), are within 2-fold of the observed values for the majority of measured cellular mRNAs (n>7000) and proteins (n>2000)...
March 15, 2018: ELife
Teresa Cruz-Bustos, Silvia N J Moreno, Roberto Docampo
Membrane proteins in trypanosomatids are, in general, weakly expressed and confirmation of their subcellular localization frequently requires their overexpression with epitope tags. However, overexpression can lead to mislocalization of the probes. Viswanathan et al. (Nat. Methods, 2015) described high performance tags for localization of weakly expressed proteins. We report here the use of these protein tags, named "spaghetti monster", for CRISPR /Cas9-mediated C-terminal endogenous tagging of Trypanosoma cruzi to localize two weakly expressed transient receptor potential (TRP) channels to acidic compartments...
March 15, 2018: Journal of Eukaryotic Microbiology
Sara Silva Pereira, Andrew P Jackson
BACKGROUND: Trypanosomatid parasites such as Trypanosoma spp. and Leishmania spp. are a major source of infectious disease in humans and domestic animals worldwide. Fundamental to the host-parasite interactions of these potent pathogens are their cell surfaces, which are highly decorated with glycosylated proteins and other macromolecules. Trypanosomatid genomes contain large multi-copy gene families encoding UDP-dependent glycosyltransferases (UGTs), the primary role of which is cell-surface decoration...
March 14, 2018: BMC Evolutionary Biology
O Villafraz, R Rondón-Mercado, A J Cáceres, J L Concepción, W Quiñones
T. rangeli epimastigotes contain only a single detectable phosphoglycerate kinase (PGK) enzyme in their cytosol. However, analysis of this parasite's recently sequenced genome showed a gene predicted to code for a PGK with the same molecular mass as the natural enzyme, and with a cytosolic localization as well. In this work, we have partially purified the natural PGK from T. rangeli epimastigotes. Furthermore, we cloned the predicted PGK gene and expressed it as a recombinant active enzyme. Both purified enzymes were kinetically characterized and displayed similar substrate affinities, with KmATP values of 0...
March 8, 2018: Experimental Parasitology
Patrícia Flávia Quaresma, Cristiana Ferreira Alves de Brito, Jeronimo Marteleto Nunes Rugani, Janaína de Moura Freire, Rodrigo de Paula Baptista, Elizabeth Castro Moreno, Raquel Carvalho Gontijo, Felipe Dutra Rego, Joaquim Edemilson Diniz, Maria Norma Melo, Célia Maria Ferreira Gontijo
American tegumentary leishmaniasis (ATL) samples obtained from the lesions of patients with typical (n = 25, 29%), atypical (n = 60, 69%) or both (n = 2%) clinical manifestations were analysed by multilocus enzyme electrophoresis, hsp70 restriction-fragment length polymorphism (PCR-RFLP), hsp70 sequencing and phylogenetics methods. The hsp70 PCR-RFLP analysis revealed two different profiles whose the most samples differed from those expected for Leishmania braziliensis and the other Leishmania species tested: of 39 samples evaluated, two (5%) had a restriction profile corresponding to L...
March 12, 2018: Parasitology
Danyil Grybchuk, Alexei Y Kostygov, Diego H Macedo, Claudia M d'Avila-Levy, Vyacheslav Yurchenko
Viruses of trypanosomatids are now being extensively studied because of their diversity and the roles they play in flagellates' biology. Among the most prominent examples are leishmaniaviruses implicated in pathogenesis of Leishmania parasites. Here, we present a historical overview of this field, starting with early reports of virus-like particles on electron microphotographs, and culminating in detailed molecular descriptions of viruses obtained using modern next generation sequencing-based techniques. Because of their diversity, different life cycle strategies and host specificity, we believe that trypanosomatids are a fertile ground for further explorations to better understand viral evolution, routes of transitions, and molecular mechanisms of adaptation to different hosts...
February 19, 2018: Memórias do Instituto Oswaldo Cruz
John I Robinson, Stephen M Beverley
Leishmania is a widespread trypanosomatid protozoan parasite causing significant morbidity and mortality in humans. The endobiont dsRNA virus Leishmania RNA virus 1 (LRV1) chronically infects some strains, where it increases parasite numbers and virulence in murine leishmaniasis models, and correlates with increased treatment failure in human disease. Previously, we reported that 2'-C-methyladenosine (2CMA) potently inhibited LRV1 in Leishmania guyanensis ( Lgy ) and L. braziliensis , leading to viral eradication at concentrations above 10 µM...
March 6, 2018: Journal of Biological Chemistry
Ludmila Ferreira de Almeida Fiuza, Raiza Brandão Peres, Marianne Rocha Simões-Silva, Patricia Bernardino da Silva, Denise da Gama Jaen Batista, Cristiane França da Silva, Aline Nefertiti Silva da Gama, Tummala Rama Krishna Reddy, Maria de Nazaré Correia Soeiro
American trypanosomiasis or Chagas disease (CD) is a vector borne pathology caused by the parasite Trypanosoma cruzi (T. cruzi), which remains a serious global health problem. The current available treatment for CD is limited to two nitroderivatives with limited efficacy and several side effects. The rational design of ergosterol synthetic route inhibitors (e.g. CYP51 inhibitors) represents a promising strategy for fungi and trypanosomatids, exhibiting excellent anti-T.cruzi activity in pre-clinical assays...
February 23, 2018: European Journal of Medicinal Chemistry
Jennifer M Holden, Ludek Koreny, Samson Obado, Alexander V Ratushny, Wei-Ming Chen, Jean-Mathieu Bart, Miguel Navarro, Brian T Chait, John D Aitchison, Michael P Rout, Mark C Field
Components of the nuclear periphery coordinate a multitude of activities, including macromolecular transport, cell-cycle progression and chromatin organization. Nuclear pore complexes (NPCs) mediate nucleocytoplasmic transport, mRNA processing and transcriptional regulation, and NPC components can define regions of high transcriptional activity in some organisms at the nuclear periphery and nucleoplasm. Lineage-specific features underpin several core nuclear functions, and in trypanosomatids, which branched very early from other eukaryotes, unique protein components constitute the lamina, kinetochores and parts of the NPCs...
March 1, 2018: Molecular Biology of the Cell
Anzhelika Butenko, Tamara da Silva Vieira, Alexander O Frolov, Fred R Opperdoes, Rodrigo P Soares, Alexei Yu Kostygov, Julius Lukeš, Vyacheslav Yurchenko
Background: Leptomonas pyrrhocoris is a parasite of the firebug Pyrrhocoris apterus. This flagellate has been recently proposed as a model species for studying different aspects of the biology of monoxenous trypanosomatids, including host - parasite interactions. During its life cycle L. pyrrhocoris never tightly attaches to the epithelium of the insect gut. In contrast, its dixenous relatives (Leishmania spp.) establish a stable infection via attachment to the intestinal walls of their insect hosts...
February 2018: Current Genomics
Santiago Martínez-Calvillo, Gabriela Romero-Meza, Juan C Vizuet-de-Rueda, Luis E Florencio-Martínez, Rebeca Manning-Cela, Tomás Nepomuceno-Mejía
The Trypanosomatid family includes flagellated parasites that cause fatal human diseases. Remarkably, protein-coding genes in these organisms are positioned in long tandem arrays that are transcribed polycistronically. However, the knowledge about regulation of transcription initiation and termination in trypanosomatids is scarce. The importance of epigenetic regulation in these processes has become evident in the last years, as distinctive histone modifications and histone variants have been found in transcription initiation and termination regions...
February 2018: Current Genomics
Francisco Macías, Raquel Afonso-Lehmann, Manuel C López, Inmaculada Gómez, M Carmen Thomas
Introduction: An important portion of the Trypanosoma cruzi genome is composed of mobile genetic elements, which are interspersed with genes on all chromosomes. The L1Tc non-LTR retrotransposon and its truncated version NARTc are the most highly represented and best studied of these elements. L1Tc is actively transcribed in all three forms of the Trypanosoma parasite and encodes the proteins that enable it to autonomously mobilize. This mini review discusses the enzymatic properties of L1Tc that enable its mobilization and possibly the mobilization of other non-autonomous retrotransposons in Trypanosoma...
February 2018: Current Genomics
Catarina A Marques, Richard McCulloch
Introduction: Understanding how the nuclear genome of kinetoplastid parasites is replicated received experimental stimulus from sequencing of the Leishmania major, Trypanosoma brucei and Trypanosoma cruzi genomes around 10 years ago. Gene annotations suggested key players in DNA replication initiation could not be found in these organisms, despite considerable conservation amongst characterised eukaryotes. Initial studies that indicated trypanosomatids might possess an archaeal-like Origin Recognition Complex (ORC), composed of only a single factor termed ORC1/CDC6, have been supplanted by the more recent identification of an ORC in T...
February 2018: Current Genomics
João Luís Reis-Cunha, Hugo O Valdivia, Daniella Castanheira Bartholomeu
Trypanosomatids are a group of kinetoplastid parasites including some of great public health importance, causing debilitating and life-long lasting diseases that affect more than 24 million people worldwide. Among the trypanosomatids, Trypanosoma cruzi, Trypanosoma brucei and species from the Leishmania genus are the most well studied parasites, due to their high prevalence in human infections. These parasites have an extreme genomic and phenotypic variability, with a massive expansion in the copy number of species-specific multigene families enrolled in host-parasite interactions that mediate cellular invasion and immune evasion processes...
February 2018: Current Genomics
Neeloo Singh, Renu Goel, Ekta Jain
PURPOSE: Although in trypanosomatids, monoxeny (Leptomonas) is ancestral to dixeny (Leishmania), however clinical cases of visceral leishmanisis with Leptomonas co-infection are increasingly being reported from India. Using a proteogenomic approach, we carried out a detailed proteome analysis of these two kinetoplastid parasites viz. Leishmania and its sister Leptomonas, to catalog the key proteins associated with and therefore possibly responsible for phenotype changes in Leptomonas evolution and domestication as co-infection with Leishmania...
February 22, 2018: Proteomics. Clinical Applications
Tarcilla C Borghesan, Marta Campaner, Tania E Matsumoto, Omar A Espinosa, Victor Razafindranaivo, Fernando Paiva, Julio C Carranza, Nestor Añez, Luis Neves, Marta M G Teixeira, Erney P Camargo
This study is about the inter- and intra-specific genetic diversity of trypanosomatids of the genus Angomonas , and their association with Calliphoridae (blowflies) in Neotropical and Afrotropical regions. Microscopic examination of 3,900 flies of various families, mostly Calliphoridae, revealed that 31% of them harbored trypanosomatids. Small subunit rRNA (SSU rRNA) barcoding showed that Angomonas predominated (46%) over the other common trypanosomatids of blowflies of genera Herpetomonas and Wallacemonas ...
2018: Frontiers in Microbiology
Kartikeya Tiwari, Vikash Kumar Dubey
The trypanosomatid parasites continue their killing spree resulting in significant annual mortality due to the lack of effective treatments and the prominence of these diseases in poorer countries. These dimorphic parasites thrive unchecked in the host system, outsmarting the immune mechanisms. An understanding of biology of these parasitic forms will help in the management and elimination of these fatal diseases. Investigation of various metabolic pathways in these parasites has shed light in the understanding of the unique biology of the trypansomatids...
February 8, 2018: Parasites & Vectors
Pasquale Linciano, Carolina B Moraes, Laura M Alcantara, Caio H Franco, Bruno Pascoalino, Lucio H Freitas-Junior, Sara Macedo, Nuno Santarem, Anabela Cordeiro-da-Silva, Sheraz Gul, Gesa Witt, Maria Kuzikov, Bernhard Ellinger, Stefania Ferrari, Rosaria Luciani, Antonio Quotadamo, Luca Costantino, Maria Paola Costi
Basing on a library of thiadiazole derivatives showing anti-trypanosomatidic activity, we have considered the thiadiazoles opened forms and reaction intermediates, thiosemicarbazones, as compounds of interest for phenotypic screening against Trypanosoma brucei (Tb), intracellular amastigote form of Leishmania infantum (Li) and Trypanosoma cruzi (Tc). Similar compounds have already shown interesting activity against the same organisms. The compounds were particularly effective against T. brucei and T. cruzi...
January 30, 2018: European Journal of Medicinal Chemistry
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