The Experts below are selected from a list of 273 Experts worldwide ranked by ideXlab platform
Lars Thelander - One of the best experts on this subject based on the ideXlab platform.
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Trypanosoma Brucei ctp synthetase a target for the treatment of african sleeping sickness
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Anders Hofer, Dietmar Steverding, Andrei Chabes, Reto Brun, Lars ThelanderAbstract:Trypanosoma Brucei CTP synthetase : a target for the treatment of African sleeping sickness.
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Allosteric regulation of Trypanosoma Brucei ribonucleotide reductase studied in vitro and in vivo.
Journal of Biological Chemistry, 1998Co-Authors: Anders Hofer, Justine T. Ekanem, Lars ThelanderAbstract:Allosteric regulation of Trypanosoma Brucei ribonucleotide reductase studied in vitro and in vivo.
Michael A. J. Ferguson - One of the best experts on this subject based on the ideXlab platform.
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comparative silac proteomic analysis of Trypanosoma Brucei bloodstream and procyclic lifecycle stages
PLOS ONE, 2012Co-Authors: Michael D Urbaniak, Lucia M S Guther, Michael A. J. FergusonAbstract:The protozoan parasite Trypanosoma Brucei has a complex digenetic lifecycle between a mammalian host and an insect vector, and adaption of its proteome between lifecycle stages is essential to its survival and virulence. We have optimized a procedure for growing Trypanosoma Brucei procyclic form cells in conditions suitable for stable isotope labeling by amino acids in culture (SILAC) and report a comparative proteomic analysis of cultured procyclic form and bloodstream form T. Brucei cells. In total we were able to identify 3959 proteins and quantify SILAC ratios for 3553 proteins with a false discovery rate of 0.01. A large number of proteins (10.6%) are differentially regulated by more the 5-fold between lifecycle stages, including those involved in the parasite surface coat, and in mitochondrial and glycosomal energy metabolism. Our proteomic data is broadly in agreement with transcriptomic studies, but with significantly larger fold changes observed at the protein level than at the mRNA level.
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Trypanosoma Brucei UDP-glucose:glycoprotein glucosyltransferase has unusual substrate specificity and protects the parasite from stress.
Eukaryotic Cell, 2008Co-Authors: Luis Izquierdo, Abdel Atrih, João A. Rodrigues, Deuan C. Jones, Michael A. J. FergusonAbstract:In this paper, we describe the range of N-linked glycan structures produced by wild-type and glucosidase II null mutant bloodstream form Trypanosoma Brucei parasites and the creation and characterization of a bloodstream form Trypanosoma Brucei UDP-glucose:glycoprotein glucosyltransferase null mutant. These analyses highlight peculiarities of the Trypanosoma Brucei UDP-glucose:glycoprotein glucosyltransferase, including an unusually wide substrate specificity, ranging from Man5GlcNAc2 to Man9GlcNAc2 glycans, and an unusually high efficiency in vivo, quantitatively glucosylating the Asn263 N-glycan of variant surface glycoprotein (VSG) 221 and 75% of all non-VSG N glycosylation sites. We also show that although Trypanosoma Brucei UDP-glucose:glycoprotein glucosyltransferase is not essential for parasite growth at 37°C, it is essential for parasite growth and survival at 40°C. The null mutant was also shown to be hypersensitive to the effects of the N glycosylation inhibitor tunicamycin. Further analysis of bloodstream form Trypanosoma Brucei under normal conditions and stress conditions suggests that it does not have a classical unfolded protein response triggered by sensing unfolded proteins in the endoplasmic reticulum. Rather, judging by its uniform Grp78/BiP levels, it appears to have an unregulated and constitutively active endoplasmic reticulum protein folding system. We suggest that the latter may be particularly appropriate for this organism, which has an extremely high flux of glycoproteins through its secretory pathway.
Annette Macleod - One of the best experts on this subject based on the ideXlab platform.
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Whole-Genome Sequencing of Trypanosoma Brucei Reveals Introgression between Subspecies That Is Associated with Virulence
Mbio, 2013Co-Authors: Ian Goodhead, Annette Macleod, Paul Capewell, J. Wendi Bailey, Tanja Beament, Michael L. Chance, Sarah N. Forrester, Mark J. Taylor, Harry NoyesAbstract:ABSTRACT Human African trypanosomiasis is caused by two subspecies of Trypanosoma Brucei. Trypanosoma Brucei rhodesiense is found in East Africa and frequently causes acute disease, while Trypanosoma Brucei gambiense is found in West Africa and is associated with chronic disease. Samples taken from a single focus of a Ugandan outbreak of T . b. rhodesiense in the 1980s were associated with either chronic or acute disease. We sequenced the whole genomes of two of these isolates, which showed that they are genetically distinct from each other. Analysis of single nucleotide polymorphism markers in a panel of 31 Ugandan isolates plus 32 controls revealed a mixture of East African and West African haplotypes, and some of these haplotypes were associated with the different virulence phenotypes. It has been shown recently that T . b. Brucei and T . b. rhodesiense populations undergo genetic exchange in natural populations. Our analysis showed that these strains from the Ugandan epidemic were intermediate between the reference genome sequences of T . b. gambiense and T . b. Brucei and contained haplotypes that were present in both subspecies. This suggests that the human-infective subspecies of T. Brucei are not genetically isolated, and our data are consistent with genomic introgression between East African and West African T . b. Brucei subspecies. This has implications for the control of the parasite, the spread of drug resistance, and understanding the variation in virulence and the emergence of human infectivity. IMPORTANCE We present a genetic study of the acute form of “sleeping sickness” caused by the protozoan parasite Trypanosoma Brucei rhodesiense from a single outbreak in Uganda. This represents an advance in our understanding of the relationship between the T . b. rhodesiense and Trypanosoma Brucei gambiense subspecies that have previously been considered geographically distinct. Our data suggest that introgression of West African-derived T. Brucei haplotypes may be associated with differences in disease presentation in the East African disease. These findings are not only of scientific interest but also important for parasite control, as they suggest that the human-infective T. Brucei subspecies are not genetically isolated.
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mechanism of Trypanosoma Brucei gambiense group 1 resistance to human trypanosome lytic factor
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Rudo Kieft, Annette Macleod, Paul Capewell, Michael C R Turner, Nicola Veitch, Stephen L HajdukAbstract:Human innate immunity against most African trypanosomes, including Trypanosoma Brucei Brucei, is mediated by a minor subclass of toxic serum HDL, called trypanosome lytic factor-1 (TLF-1). This HDL contains two primate specific proteins, apolipoprotein L-1 and haptoglobin (Hp)-related protein, as well as apolipoprotein A-1. These assembled proteins provide a powerful defense against trypanosome infection. Trypanosoma Brucei rhodesiense causes human African sleeping sickness because it has evolved an inhibitor of TLF-1, serum resistance-associated (SRA) protein. Trypanosoma Brucei gambiense lacks the SRA gene, yet it infects humans. As transfection of T. b. gambiense (group 1) is not possible, we initially used in vitro-selected TLF-1–resistant T. b. Brucei to examine SRA-independent mechanisms of TLF-1 resistance. Here we show that TLF-1 resistance in T. b. Brucei is caused by reduced expression of the Hp/Hb receptor gene (TbbHpHbR). Importantly, T. b. gambiense (group 1) also showed a marked reduction in uptake of TLF-1 and a corresponding decrease in expression of T. b. gambiense Hp/Hb receptor (TbgHpHbR). Ectopic expression of TbbHpHbR in TLF-1–resistant T. b. Brucei rescued TLF-1 uptake, demonstrating that decreased TbbHpHbR expression conferred TLF-1 resistance. Ectopic expression of TbgHpHbR in TLF-1–resistant T. b. Brucei failed to rescue TLF-1 killing, suggesting that coding sequence changes altered Hp/Hb receptor binding affinity for TLF-1. We propose that the combination of coding sequence mutations and decreased expression of TbgHpHbR directly contribute to parasite evasion of human innate immunity and infectivity of group 1 T. b. gambiense.
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Genetic analysis of the human infective trypanosome Trypanosoma Brucei gambiense: chromosomal segregation, crossing over, and the construction of a genetic map
Genome Biology, 2008Co-Authors: Anneli Cooper, Andy Tait, Lindsay Sweeney, Alison Tweedie, Liam J. Morrison, C. Michael R. Turner, Annette MacleodAbstract:Background Trypanosoma Brucei is the causative agent of human sleeping sickness and animal trypanosomiasis in sub-Saharan Africa, and it has been subdivided into three subspecies: Trypanosoma Brucei gambiense and Trypanosoma Brucei rhodesiense, which cause sleeping sickness in humans, and the nonhuman infective Trypanosoma Brucei Brucei. T. b. gambiense is the most clinically relevant subspecies, being responsible for more than 90% of all Trypanosomal disease in humans. The genome sequence is now available, and a Mendelian genetic system has been demonstrated in T. Brucei, facilitating genetic analysis in this diploid protozoan parasite. As an essential step toward identifying loci that determine important traits in the human-infective subspecies, we report the construction of a high-resolution genetic map of the STIB 386 strain of T. b. gambiense.
John C Meade - One of the best experts on this subject based on the ideXlab platform.
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artemisinins inhibit Trypanosoma cruzi and Trypanosoma Brucei rhodesiense in vitro growth
Antimicrobial Agents and Chemotherapy, 2007Co-Authors: Yuliya V Mishina, Sanjeev Krishna, Richard K Haynes, John C MeadeAbstract:Artemisinin compounds inhibit in vitro growth of cultured Trypanosoma cruzi and Trypanosoma Brucei rhodesiense at concentrations in the low micromolar range. Artemisinin also inhibits calcium-dependent ATPase activity in T. cruzi membranes, suggesting a mode of action via membrane pumps. Artemisinins merit further investigation as chemotherapeutic options for these pathogens.
Miguel Navarro - One of the best experts on this subject based on the ideXlab platform.
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Localization of serum resistance-associated protein in Trypanosoma Brucei rhodesiense and transgenic Trypanosoma Brucei Brucei.
Cellular Microbiology, 2015Co-Authors: Jean-mathieu Bart, Mark Carrington, Carlos Cordon-obras, Isabel Vidal, Jennifer Reed, Esperanza Perez-pastrana, Laureano Cuevas, Mark C. Field, Miguel NavarroAbstract:Summary African trypanosomes infect a broad range of mammals, but humans and some higher primates are protected by serum trypanosome lytic factors that contain apolipoprotein L1 (ApoL1). In the human-infective subspecies of Trypanosoma Brucei, Trypanosoma Brucei rhodesiense, a gene product derived from the variant surface glycoprotein gene family member, serum resistance-associated protein (SRA protein), protects against ApoL1-mediated lysis. Protection against trypanosome lytic factor requires the direct interaction between SRA protein and ApoL1 within the endocytic apparatus of the trypanosome, but some uncertainty remains as to the precise mechanism and location of this interaction. In order to provide more insight into the mechanism of SRA-mediated resistance to trypanosome lytic factor, we assessed the localization of SRA in T. b. rhodesiense EATRO3 using a novel monoclonal antibody raised against SRA together with a set of well-characterized endosomal markers. By three-dimensional deconvolved immunofluorescence single-cell analysis, combined with double-labelling immunoelectron microscopy, we found that ≈ 50% of SRA protein localized to the lysosome, with the remaining population being distributed through the endocytic pathway, but apparently absent from the flagellar pocket membrane. These data suggest that the SRA/trypanolytic factor interaction is intracellular, with the concentration within the endosomes potentially crucial for ensuring a high efficiency.
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diamine and aminoalcohol derivatives active against Trypanosoma Brucei
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Esther Del Olmo, Rosario Diazgonzalez, Ricardo Escarcena, Luis Carvalho, Luis A Bustos, Miguel Navarro, Arturo San FelicianoAbstract:Abstract Twenty compounds selected as representative members of three series of long-chain 1,2-diamines, 2-amino-1-alkanols and 1-amino-2-alkanols structurally related to dihydrosphingosin, were synthesized and tested in vitro for their ability to inhibit the sleeping sickness parasites Trypanosoma Brucei rhodesiense and Trypanosoma Brucei gambiense . Eight compounds showed EC 50 values in the submicromolar range, with selectivity indexes up to 39 related to the respective cytotoxicity values for Vero cells. The parasite phenotype detected after treatment with the most potent compounds showed irreversible cell morphology alterations of the flagellar pocket that lead to inhibition of cell growth and parasite death.
