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Sent on Wednesday, 2010 Apr 21Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | Parasitol Res. 2010 Apr 20. [Epub ahead of print]Leishmania mexicana promastigotes secrete a protein tyrosine phosphatase.Escalona-Montaño AR, Pardavé-Alejandre D, Cervantes-Sarabia R, García-López P, Gutiérrez-Quiroz M, Gutiérrez-Kobeh L, Becker-Fauser I, Aguirre-García MM.Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Dr. Balmis 148, Colonia Doctores, México D.F., 06726, México, almiusqfb23@yahoo.com.mx. AbstractLeishmania mexicana is an intracellular protozoan parasite that infects macrophages and dendritic cells and causes a chronic cutaneous disease. Although many enzymatic activities have been reported in this parasite, the presence of kinases and phosphatases has been poorly studied. These enzymes control the phosphorylation and dephosphorylation of proteins. Specifically, protein tyrosine kinases phosphorylate tyrosine residues and protein tyrosine phosphatases (PTPases) dephosphorylate tyrosine residues. PTPase activities have been reported as pathogenic factors in various infectious microorganisms such as viruses, bacteria, and parasites. Also, it has been shown that the induction of one or more PTPase activities in macrophages represents an important pathogenicity factor in Leishmania. Recently, we reported a membrane-bound PTPase activity in promastigotes of Leishmania major. In the present work, we give evidence that promastigotes of L. mexicana are able to secrete a PTPase into the culture medium. Two antibodies: one monoclonal against the catalytic domains of the human placental PTPase 1B and a polyclonal rabbit anti-recombinant protein Petase7 from Trypanosoma brucei cross-reacted with a 50-kDa molecule. The anti-human PTPase 1B antibody depleted the enzymatic activity present in the conditioned medium. The pattern of sensitivity and resistance to specific PTPase and serine/threonine inhibitors showed that this enzyme is a protein tyrosine phosphatase. |
| PMID: 20405143 [PubMed - as supplied by publisher] | |
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| 2. | PLoS Negl Trop Dis. 2010 Apr 13;4(4):e659.A target-based high throughput screen yields Trypanosoma brucei hexokinase small molecule inhibitors with antiparasitic activity.Sharlow ER, Lyda TA, Dodson HC, Mustata G, Morris MT, Leimgruber SS, Lee KH, Kashiwada Y, Close D, Lazo JS, Morris JC.University of Pittsburgh Drug Discovery Institute and Pittsburgh Molecular Libraries Screening Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. AbstractBACKGROUND: The parasitic protozoan Trypanosoma brucei utilizes glycolysis exclusively for ATP production during infection of the mammalian host. The first step in this metabolic pathway is mediated by hexokinase (TbHK), an enzyme essential to the parasite that transfers the gamma-phospho of ATP to a hexose. Here we describe the identification and confirmation of novel small molecule inhibitors of bacterially expressed TbHK1, one of two TbHKs expressed by T. brucei, using a high throughput screening assay. METHODOLOGY/PRINCIPAL FINDINGS: Exploiting optimized high throughput screening assay procedures, we interrogated 220,233 unique compounds and identified 239 active compounds from which ten small molecules were further characterized. Computation chemical cluster analyses indicated that six compounds were structurally related while the remaining four compounds were classified as unrelated or singletons. All ten compounds were approximately 20-17,000-fold more potent than lonidamine, a previously identified TbHK1 inhibitor. Seven compounds inhibited T. brucei blood stage form parasite growth (0.03<or=EC(50)<3 microM) with parasite specificity of the compounds being demonstrated using insect stage T. brucei parasites, Leishmania promastigotes, and mammalian cell lines. Analysis of two structurally related compounds, ebselen and SID 17387000, revealed that both were mixed inhibitors of TbHK1 with respect to ATP. Additionally, both compounds inhibited parasite lysate-derived HK activity. None of the compounds displayed structural similarity to known hexokinase inhibitors or human African trypanosomiasis therapeutics. CONCLUSIONS/SIGNIFICANCE: The novel chemotypes identified here could represent leads for future therapeutic development against the African trypanosome. |
| PMID: 20405000 [PubMed - in process] | |
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| 3. | PLoS Negl Trop Dis. 2010 Apr 13;4(4):e658.The genome sequence of Trypanosoma brucei gambiense, causative agent of chronic human african trypanosomiasis.Jackson AP, Sanders M, Berry A, McQuillan J, Aslett MA, Quail MA, Chukualim B, Capewell P, MacLeod A, Melville SE, Gibson W, Barry JD, Berriman M, Hertz-Fowler C.Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom. AbstractBACKGROUND: Trypanosoma brucei gambiense is the causative agent of chronic Human African Trypanosomiasis or sleeping sickness, a disease endemic across often poor and rural areas of Western and Central Africa. We have previously published the genome sequence of a T. b. brucei isolate, and have now employed a comparative genomics approach to understand the scale of genomic variation between T. b. gambiense and the reference genome. We sought to identify features that were uniquely associated with T. b. gambiense and its ability to infect humans. METHODS AND FINDINGS: An improved high-quality draft genome sequence for the group 1 T. b. gambiense DAL 972 isolate was produced using a whole-genome shotgun strategy. Comparison with T. b. brucei showed that sequence identity averages 99.2% in coding regions, and gene order is largely collinear. However, variation associated with segmental duplications and tandem gene arrays suggests some reduction of functional repertoire in T. b. gambiense DAL 972. A comparison of the variant surface glycoproteins (VSG) in T. b. brucei with all T. b. gambiense sequence reads showed that the essential structural repertoire of VSG domains is conserved across T. brucei. CONCLUSIONS: This study provides the first estimate of intraspecific genomic variation within T. brucei, and so has important consequences for future population genomics studies. We have shown that the T. b. gambiense genome corresponds closely with the reference, which should therefore be an effective scaffold for any T. brucei genome sequence data. As VSG repertoire is also well conserved, it may be feasible to describe the total diversity of variant antigens. While we describe several as yet uncharacterized gene families with predicted cell surface roles that were expanded in number in T. b. brucei, no T. b. gambiense-specific gene was identified outside of the subtelomeres that could explain the ability to infect humans. |
| PMID: 20404998 [PubMed - in process] | |
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| 4. | PLoS One. 2010 Apr 9;5(4):e10107.Quantification of parasite load in clinical samples of leishmaniasis patients: IL-10 level correlates with parasite load in visceral leishmaniasis.Verma S, Kumar R, Katara GK, Singh LC, Negi NS, Ramesh V, Salotra P.Institute of Pathology (ICMR), Safdarjung Hospital Campus, New Delhi, India. AbstractA rapid and accurate method to detect and quantify Leishmania parasite is urgently needed to facilitate early diagnosis of leishmaniasis and monitoring of antileishmania therapy. In this study, real-time assay was applied to estimate parasite load in clinical samples of visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL) patients. The mean parasite load in blood of VL patients (n = 31) was 8,372 parasites/ml, while the mean parasite load in bone marrow aspirate (BMA) was 194,962 parasites/million nucleated cells (n = 12). Parasite load was undetectable after treatment with amphotericin B (n = 9) in VL, while a residual parasite burden was detected in 2 of 6 patients following treatment with sodium antimony gluconate. Further, circulating levels of IFN-gamma, TNF-alpha, IL-10, IL-6, IL-4 and IL-2 were analysed in VL patients (n = 29) by Cytometric Bead Array to evaluate correlation with parasitic load. Interestingly, IL-10 levels correlated significantly with parasite load (r = 0.82, P<0.0001). The mean parasite load in dermal lesions of PKDL patients was 9,502 parasites/microg tissue DNA at pre-treatment stage (n = 25), with no detectable parasites after therapy (n = 5). Parasite burden was distinctly higher (P<0.0001) in nodular lesions (n = 12) (19,586 parasites/microg tissue DNA) compared to papular/macular lesions (n = 13, 193 parasites/microg tissue DNA). Further, chronic PKDL lesions showed significantly (P = 0.0166) higher parasite load in comparison with acute lesions. Results indicate that chronic, nodular cases constitute the major parasite reservoir for anthroponotic transmission. Our results establish that the high parasite load in VL is strongly correlated with a high level of IL-10, implicating IL-10 as a marker of disease severity. The assay is applicable for diagnosis as well as prognosis of both VL and PKDL, providing a simple molecular tool to monitor the efficacy of antileishmanial drugs or vaccines. |
| PMID: 20404924 [PubMed - in process] | |
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| 5. | J Immunol. 2010 Apr 19. [Epub ahead of print]CCR2 Plays a Critical Role in Dendritic Cell Maturation: Possible Role of CCL2 and NF-{kappa}B.Jimenez F, Quinones MP, Martinez HG, Estrada CA, Clark K, Garavito E, Ibarra J, Melby PC, Ahuja SS.Audie L. Murphy Division, Veterans Administration Center for Research on AIDS and HIV-1 Infection, South Texas Veterans Health Care System. AbstractWe postulated that CCR2-driven activation of the transcription factor NF-kappaB plays a critical role in dendritic cell (DC) maturation (e.g., migration, costimulation, and IL-12p70 production), necessary for the generation of protective immune responses against the intracellular pathogen Leishmania major. Supporting this notion, we found that CCR2, its ligand CCL2, and NF-kappaB were required for CCL19 production and adequate Langerhans cell (LC) migration both ex vivo and in vivo. Furthermore, a role for CCR2 in upregulating costimulatory molecules was indicated by the reduced expression of CD80, CD86, and CD40 in Ccr2(-/-) bone marrow-derived dendritic cells (BMDCs) compared with wild-type (WT) BMDCs. Four lines of evidence suggested that CCR2 plays a critical role in the induction of protective immunity against L. major by regulating IL-12p70 production and migration of DC populations such as LCs. First, compared with WT, Ccr2(-/-) lymph node cells, splenocytes, BMDCs, and LCs produced lower levels of IL-12p70 following stimulation with LPS/IFN-gamma or L. major. Second, a reduced number of LCs carried L. major from the skin to the draining lymph nodes in Ccr2(-/-) mice compared with WT mice. Third, early treatment with exogenous IL-12 reversed the susceptibility to L. major infection in Ccr2(-/-) mice. Finally, disruption of IL-12p70 in radioresistant cells, such as LCs, but not in BMDCs resulted in the inability to mount a fully protective immune response in bone marrow chimeric mice. Collectively, our data point to an important role for CCR2-driven activation of NF-kappaB in the regulation of DC/LC maturation processes that regulate protective immunity against intracellular pathogens. |
| PMID: 20404272 [PubMed - as supplied by publisher] | |
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| 6. | Proc Natl Acad Sci U S A. 2010 Apr 19. [Epub ahead of print]Phosphoproteom e dynamics reveal heat-shock protein complexes specific to the Leishmania donovani infectious stage.Morales MA, Watanabe R, Dacher M, Chafey P, Osorio Y Fortéa J, Scott DA, Beverley SM, Ommen G, Clos J, Hem S, Lenormand P, Rousselle JC, Namane A, Späth GF.Institut Pasteur, G5 Virulence Parasitaire, 75015 Paris, France; Institut National de la Santé et de la Recherche Médicale AVENIR and Centre National de la Recherche Scientifique (Unité de Recherche Associée 2581), 75015 Paris, France. AbstractLeishmania is exposed to a sudden increase in environmental temperature during the infectious cycle that triggers stage differentiation and adapts the parasite phenotype to intracellular survival in the mammalian host. The absence of classical promoter-dependent mechanisms of gene regulation and constitutive expression of most of the heat-shock proteins (HSPs) in these human pathogens raise important unresolved questions as to regulation of the heat-shock response and stage-specific functions of Leishmania HSPs. Here we used a gel-based quantitative approach to assess the Leishmania donovani phosphoproteome and revealed that 38% of the proteins showed significant stage-specific differences, with a strong focus of amastigote-specific phosphoproteins on chaperone function. We identified STI1/HOP-containing chaperone complexes that interact with ribosomal client proteins in an amastigote-specific manner. Genetic analysis of STI1/HOP phosphorylation sites in conditional sti1(-/-) null mutant parasites revealed two phosphoserine residues essential for parasite viability. Phosphorylation of the major Leishmania chaperones at the pathogenic stage suggests that these proteins may be promising drug targets via inhibition of their respective protein kinases. |
| PMID: 20404152 [PubMed - as supplied by publisher] | |
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| 7. | Bioorg Med Chem. 2010 Mar 27. [Epub ahead of print]Synthesis and antiprotozoal activity of 2,5-bis[amidinoaryl]thiazoles.Branowska D, Farahat AA, Kumar A, Wenzler T, Brun R, Liu Y, Wilson WD, Boykin DW.Department of Chemistry, Georgia State University, Atlanta, GA 30303-3083, USA. AbstractSeven novel diamidino 2,5-bis(aryl)thiazoles (5a-g) were synthesized and evaluated against Trypanosoma brucei rhodensiense (T. b. r.) and Plasmodium falciparum (P. f.). The diamidines were obtained directly from the corresponding bis-nitriles (4a-g) by the action of lithium bis(trimethylsilyl)amide. The bis-nitriles 4a-f were synthesized in four steps starting with the Stille coupling of 2-tributyltinthiazole with the appropriate cyanoaryl halide. The bis-nitrile 5g was obtained by the palladium facilitated coupling of the mixed tin-silyl reagent 2-trimethylsilyl-5-trimethyltinthiazole with 2-bromo-5-cyanopyridine. The amidoxime potential prodrugs 6a-e, 6g were obtained by the reaction of hydroxylamine with the bis-nitriles. O-Methylation of the amidoximes gave the corresponding N-methoxyamidines 7a-c, 7e, 7g. The diamidines showed strong DNA binding affinity as reflected by DeltaT(m) measurements. Four of the diamidines 5a, 5b, 5d and 5e were highly active in vitro against P. f. giving IC(50) values between 1.1 and 2.5nM. The same four diamidines showed IC(50) values between 4 and 6nM against T. b. r. The selectivity indices ranged from 233 to 9175. One diamidine 5a produced one of four cures at an ip dose of 4x5mg/kg in the STIB900 mouse model for acute African trypanosomiasis. The amidoxime and N-methoxyamidine of 5a were the only produgs to provide cures (1/4 cures) in the same mouse model on oral dosage at 4x25mg/kg. Copyright © 2010 Elsevier Ltd. All rights reserved. |
| PMID: 20403703 [PubMed - as supplied by publisher] | |
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| 8. | Int J Antimicrob Agents. 2010 Apr 17. [Epub ahead of print]Efficacy of artemisinin in experimental visceral leishmaniasis.Sen R, Ganguly S, Saha P, Chatterjee M.Department of Pharmacology, Institute of Post Graduate Medical Education and Research, 244 B, Acharya Jagadish Chandra Bose Road, Kolkata 700 020, West Bengal, India. AbstractVisceral leishmaniasis (VL), caused by the protozoan Leishmania sp., affects 500000 people annually, with the Indian subcontinent contributing a significant proportion of these cases. Emerging refractoriness to conventional antimony therapy has emphasised the need for safer yet effective antileishmanial drugs. Artemisinin, a widely used antimalarial, demonstrated anti-promastigote activity and the 50% inhibitory concentration (IC(50)) ranged from 100muM to 120muM irrespective of Leishmania species studied. Leishmaniadonovani-infected macrophages demonstrated decreased production of nitrite as well as mRNA expression of inducible nitric oxide synthase, which was normalised by artemisinin, indicating that it exerted both a direct parasiticidal activity as well as inducing a host protective response. Furthermore, in a BALB/c model of VL, orally administered artemisinin (10mg/kg and 25mg/kg body weight) effectively reduced both splenic weight and parasite burden, which was accompanied by a restoration of Th1 cytokines (interferon-gamma and interleukin-2). Taken together, these findings have delineated the therapeutic potential of artemisinin in experimental VL. Copyright © 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. |
| PMID: 20403680 [PubMed - as supplied by publisher] | |
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| 9. | J Mol Biol. 2010 Apr 16. [Epub ahead of print]Structure of the Mitochondr ial Editosome-like Complex Associated TUTase 1 Reveals Divergent Mechanisms of UTP Selection and Domain Organization.Stagno J, Aphasizheva I, Bruystens J, Luecke H, Aphasizhev R.Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA; Center for Biomembrane Systems, University of California, Irvine, CA 92697, USA. AbstractRNA uridylylation reactions catalyzed by terminal uridylyl transferases (TUTases) play critical roles in the formation of the mitochondrial transcriptome in trypanosomes. Two mitochondrial RNA editing TUTases have been described: RET1 catalyzes gRNA, rRNA and mRNA 3'-uridylylation and RET2 acts as a subunit of the RNA editing core complex, or the 20S editosome, to perform guided U-insertion mRNA editing. Although RET1 and RET2 carry out distinct functions and possess dissimilar enzymatic properties, their catalytic N-terminal (NTD) and base-recognition C-terminal (CTD) domains display a high degree of similarity while their middle domains are less conserved. Mitochondrial Editosome-like Complex Associated TUTase 1 (MEAT1), which interacts with an editosome-like assembly and is exclusively U-specific, nonetheless shows limited similarity with editing TUTases and lacks the middle domain. The crystal structures of apo and UTP-bound MEAT1 refined to 1.56 A and 1.95 A, respectively, reveal an unusual mechanism of UTP selection and domain organization previously unseen in TUTases. In addition to established invariant UTP-binding determinants, we have identified and verified by mutagenesis critical contributions of MEAT1-specific residues. Furthermore, MEAT1 possesses a novel bridging domain (BD), which extends from the CTD and makes hydrophobic contacts with the NTD, thereby creating a cavity adjacent to the UTP-binding site. Unlike the minimal TUT4 TUTase, MEAT1 shows no appreciable conformational change upon UTP binding and apparently does not require RNA substrate to select a cognate nucleoside triphosphate. Because MEAT1 is essential for viability of bloodstream and insect forms of Trypanosoma brucei, the unique organization of its active site renders this protein an attractive target for trypanocide development. Copyright © 2010. Published by Elsevier Ltd. |
| PMID: 20403364 [PubMed - as supplied by publisher] | |
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| 10. | Euro Surveill. 2010 Mar 11;15(10):19505.Leishmaniasis emergence in Europe.Ready PD.Department of Entomology, Natural History Museum, London, United Kingdom. P.Ready@nhm.ac.uk AbstractLeishmaniasis emergence in Europe is reviewed, based on a search of literature up to and including 2009. Topics covered are the disease, its relevance, transmission and epidemiology, diagnostic methods, treatment, prevention, current geographical distribution, potential factors triggering changes in distribution, and risk prediction. Potential factors triggering distribution changes include vectorial competence, importation or dispersal of vectors and reservoir hosts, travel, and climatic/environmental change. The risk of introducing leishmaniasis into the European Union (EU) and its spread among Member States was assessed for the short (2-3 years) and long term (15-20 years). There is only a low risk of introducing exotic Leishmania species because of the absence of proven vectors and/or reservoir hosts. The main threat comes from the spread of the two parasites endemic in the EU, namely Leishmania infantum, which causes zoonotic visceral and cutaneous leishmaniasis in humans and the domestic dog (the reservoir host), and L. tropica, which causes anthroponotic cutaneous leishmaniasis. The natural vector of L. tropica occurs in southern Europe, but periodic disease outbreaks in Greece (and potentially elsewhere) should be easily contained by surveillance and prompt treatment, unless dogs or other synanthropic mammals prove to be reservoir hosts. The northward spread of L. infantum from the Mediterranean region will depend on whether climate and land cover permit the vectors to establish seasonal biting rates that match those of southern Europe. Increasing dog travel poses a significant risk of introducing L. infantum into northern Europe, and the threat posed by non-vectorial dog-to-dog transmission should be investigated. |
| PMID: 20403308 [PubMed - in process] | |
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