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Sent on Thursday, 2012 January 26Search: kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | PLoS One. 2012;7(1):e28266. Epub 2012 Jan 20.First Detection of Leishmania major DNA in Sergentomyia (Spelaeomyia) darlingi from Cutaneous Leishmaniasis Foci in Mali.Berdjane-Brouk Z, Koné AK, Djimdé AA, Charrel RN, Ravel C, Delaunay P, Del Giudice P, Diarra AZ, Doumbo S, Goita S, Thera MA, Depaquit J, Marty P, Doumbo OK, Izri A.SourceParasitologie, Hôpital Avicenne, Université de Paris 13, Paris, France. AbstractBACKGROUND:Leishmania major complex is the main causative agent of zoonotic cutaneous leishmaniasis (ZCL) in the Old World. Phlebotomus papatasi and Phlebotomus duboscqi are recognized vectors of L. major complex in Northern and Southern Sahara, respectively. In Mali, ZCL due to L. major is an emerging public health problem, with several cases reported from different parts of the country. The main objective of the present study was to identify the vectors of Leishmania major in the Bandiagara area, in Mali. METHODOLOGY/PRINCIPAL FINDINGS:An entomological survey was carried out in the ZCL foci of Bandiagara area. Sandflies were collected using CDC miniature light traps and sticky papers. In the field, live female Phlebotomine sandflies were identified and examined for the presence of promastigotes. The remaining sandflies were identified morphologically and tested for Leishmania by PCR in the ITS2 gene. The source of blood meal of the engorged females was determined using the cyt-b sequence. Out of the 3,259 collected sandflies, 1,324 were identified morphologically, and consisted of 20 species, of which four belonged to the genus Phlebotomus and 16 to the genus Sergentomyia. Leishmania major DNA was detected by PCR in 7 of the 446 females (1.6%), specifically 2 out of 115 Phlebotomus duboscqi specimens, and 5 from 198 Sergentomyia darlingi specimens. Human DNA was detected in one blood-fed female S. darlingi positive for L. major DNA. CONCLUSION:Our data suggest the possible involvement of P. duboscqi and potentially S. darlingi in the transmission of ZCL in Mali. |
| 2. | PLoS Pathog. 2012 Jan;8(1):e1002417. Epub 2012 Jan 19.Progressive Visceral Leishmaniasis Is Driven by Dominant Parasite-induced STAT6 Activation and STAT6-dependent Host Arginase 1 Expression.Osorio EY, Zhao W, Espitia C, Saldarriaga O, Hawel L, Byus CV, Travi BL, Melby PC.SourceResearch Service, Department of Veterans Affairs Medical Center, South Texas Veterans Health Care System, San Antonio, Texas, United States of America. AbstractThe clinicopathological features of the hamster model of visceral leishmaniasis (VL) closely mimic active human disease. Studies in humans and hamsters indicate that the inability to control parasite replication in VL could be related to ineffective classical macrophage activation. Therefore, we hypothesized that the pathogenesis of VL might be driven by a program of alternative macrophage activation. Indeed, the infected hamster spleen showed low NOS2 but high arg1 enzyme activity and protein and mRNA expression (p<0.001) and increased polyamine synthesis (p<0.05). Increased arginase activity was also evident in macrophages isolated from the spleens of infected hamsters (p<0.05), and arg1 expression was induced by L. donovani in primary hamster peritoneal macrophages (p<0.001) and fibroblasts (p<0.01), and in a hamster fibroblast cell line (p<0.05), without synthesis of endogenous IL-4 or IL-13 or exposure to exogenous cytokines. miRNAi-mediated selective knockdown of hamster arginase 1 (arg1) in BHK cells led to increased generation of nitric oxide and reduced parasite burden (p<0.005). Since many of the genes involved in alternative macrophage activation are regulated by Signal Transducer and Activator of Transcription-6 (STAT6), and because the parasite-induced expression of arg1 occurred in the absence of exogenous IL-4, we considered the possibility that L. donovani was directly activating STAT6. Indeed, exposure of hamster fibroblasts or macrophages to L. donovani resulted in dose-dependent STAT6 activation, even without the addition of exogenous cytokines. Knockdown of hamster STAT6 in BHK cells with miRNAi resulted in reduced arg1 mRNA expression and enhanced control of parasite replication (p<0.0001). Collectively these data indicate that L. donovani infection induces macrophage STAT6 activation and STAT6-dependent arg1 expression, which do not require but are amplified by type 2 cytokines, and which contribute to impaired control of infection. |
| 3. | J Cell Sci. 2012 Jan 24. [Epub ahead of print]Structure-function relationship of the Polo-like kinase in Trypanosoma brucei.Yu Z, Liu Y, Li Z.AbstractPolo-like kinases (Plks) play multiple roles in mitosis and cytokinesis in eukaryotes and are characterized by the C-terminal Polo-box domain (PBD) implicated in binding to Plk substrates, targeting Plk, and regulating Plk activity. The Plk homolog in Trypanosoma brucei possesses a similar architecture, but it lacks the crucial residues involved in substrate binding and regulates cytokinesis but not mitosis. Despite these, little is known about the regulation of TbPLK and the role of the PBD in TbPLK localization and function. Here, we addressed the requirement of the kinase activity and the PBD for TbPLK localization and function through coupling RNAi of endogenous TbPLK with ectopic expression of TbPLK mutants. We demonstrate that the kinase activity and phosphorylation of two threonine residues, Thr198 and Thr202, in the activation loop (T-loop) of the kinase domain are essential for TbPLK function but not for TbPLK localization. Deletion of the PBD abolishes TbPLK localization, but the PBD itself is not correctly targeted, indicating that TbPLK localization requires both the PBD and the kinase domain. Surprisingly, the kinase domain of TbPLK, but not the PBD, binds to its substrates, TbCentrin2 and p110, suggesting that TbPLK may interact with its substrate through different mechanisms. Finally, the PBD interacts with the kinase domain of TbPLK and inhibits its activity, and this inhibition is relieved when Thr198 is phosphorylated. Together, these results suggest an essential role of T-loop phosphorylation in TbPLK activation and crucial roles of the PBD in regulating TbPLK activity and localization. |
| 4. | J Biol Chem. 2012 Jan 23. [Epub ahead of print]High-throughput screening against the peroxidase cascade of African trypanosomes identifies antiparasitic compounds that inactivate tryparedoxin.Fueller F, Jehle B, Putzker K, Lewis JD, Krauth-Siegel RL.SourceBiochemie-Zentrum der Universitaet Heidelberg, Germany; AbstractIn African trypanosomes, the detoxification of broad-spectrum hydroperoxides relies on a unique cascade composed of trypanothione [T(SH)2], trypanothione reductase (TR), tryparedoxin (Tpx) and nonselenium glutathione peroxidase-type enzymes (Px). All three proteins are essential for Trypanosoma brucei. Here we subjected the complete system to a high-throughput screening approach with nearly 80,000 chemicals. Twelve compounds inhibited the peroxidase system. Except one, all of them carried chloroalkyl substituents. The detailed kinetic analysis showed that two compounds weakly inhibited TR but none of them specifically interacted with the peroxidase. They proved to be time-dependent inhibitors of Tpx modifying Cys40, the first cysteine of its active site WCPPC motif. Importantly, gel shift assays verified Tpx as target in the intact parasites. T(SH)2, present in the in vitro assays and in the cells in high molar excess, did not interfere with Tpx inactivation. The compounds inhibited the proliferation of bloodstream T. brucei with EC50-values down to <1 microM and exerted up to 83-fold lower toxicity towards HeLa cells. Irreversible inhibitors are traditionally regarded as unfavourable. However, a large number of antimicrobials and anticancer therapeutics act covalently with their target protein. The compounds identified here also interacted with recombinant human thioredoxin, a distant relative of Tpx. This finding might even be exploited for thioredoxin-based anticancer drug development approaches reported recently. The fact that the T(SH)2/Tpx couple occupies a central position within the trypanosomal thiol metabolism and delivers electrons also for the synthesis of DNA precursors, renders the parasite-specific oxidoreductase an attractive drug target molecule. |
| 5. | Proteins. 2011 Dec 22. doi: 10.1002/prot.24019. [Epub ahead of print]Insights into internal dynamics of 6-phosphogluconolactonase from trypanosoma brucei studied by NMR and molecular dynamics.Calligari PA, Salgado GF, Pelupessy P, Lopes P, Ouazzani J, Bodenhausen G, Abergel D.SourceDépartement de Chimie, Ecole Normale Supérieure, 24 rue Lhomond, 75231 Paris Cedex 05, France; Université Pierre-et-Marie Curie, Place Jussieu, 75005 Paris, France; UMR 7203 CNRS, 24 rue Lhomond, 75231 Paris Cedex 05, France. AbstractNuclear magnetic resonance (NMR) is used to investigate the backbone dynamics in 6-phosphogluconolactonase from T. brucei (Tb6PGL) with (holo-) and without (apo-) 6-phosphogluconic acid (6PGA) as ligand. Relaxation data were analyzed using the model-free (MF) approach and reduced spectral density mapping (SDM). Comparison of predictions, based on 77 ns molecular dynamics (MD) simulations, with the observed relaxation rates gives insight into dynamical properties of the protein and their alteration upon ligand binding. Data indicate dynamics changes in the vicinity of the binding site. Maybe more interesting is the presence of perturbations located in remote regions of this well-structured globular protein in which no large amplitude regional motion is involved. This is reminiscent of other studies in the literature, and suggests that delocalized dynamics changes upon binding could be a general feature of protein-target interactions. Proteins 2011. © 2011 Wiley-Liss, Inc. Copyright © 2011 Wiley-Liss, Inc. |
| 6. | Exp Parasitol. 2012 Jan;130(1):13-21. Epub 2011 Oct 19.Differential expression of cruzipain- and gp63-like molecules in the phytoflagellate trypanosomatid Phytomonas serpens induced by exogenous proteins.Elias CG, Chagas MG, Souza-Gonçalves AL, Pascarelli BM, d'Avila-Levy CM, Branquinha MH, Santos AL.SourceLaboratório de Estudos Integrados em Bioquímica Microbiana, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Bloco E-subsolo, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Av Carlos Chagas Filho, 373 Cidade Universitária, Rio de Janeiro 21941-902, Brazil. AbstractPhytomonas serpens synthesizes metallo- and cysteine-proteases that are related to gp63 and cruzipain, respectively, two virulence factors produced by pathogenic trypanosomatids. Here, we described the cellular distribution of gp63- and cruzipain-like molecules in P. serpens through immunocytochemistry and confocal fluorescence microscopy. Both proteases were detected in distinct cellular compartments, presenting co-localization in membrane domains and intracellular regions. Subsequently, we showed that exogenous proteins modulated the production of both protease classes, but in different ways. Regarding the metalloprotease, only fetal bovine serum (FBS) influenced the gp63 expression, reducing its surface exposition (≈30%). Conversely, the cruzipain-like molecule was differentially modulated according to the proteins: human and bovine albumins reduced its expression around 50% and 35%, respectively; mucin and FBS did not alter its production, while IgG and hemoglobin drastically enhanced its surface exposition around 7- and 11-fold, respectively. Additionally, hemoglobin induced an augmentation in the cell-associated cruzipain-like activity in a dose-dependent manner. A twofold increase of the secreted cruzipain-like protein was detected after parasite incubation with 1% hemoglobin compared to the parasites incubated in PBS-glucose. The results showed the ability of P. serpens in modulating the expression and the activity of proteolytic enzymes after exposition to exogenous proteins, with emphasis in its cruzipain-like molecules. Copyright © 2011 Elsevier Inc. All rights reserved. |
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| 7. | Homeopathy. 2011 Oct;100(4):237-43.Different forms of administration of biotherapy 7dH in mice experimentally infected by Trypanosoma cruzi pr oduce different effects.Ferraz FN, Simoni GK, do Nascimento A, de Melo CS, Aleixo DL, Gomes ML, Spack M, de Araújo SM.SourceBasic Health Science Department, Universidade Estadual de Maringá, Paraná, Brazil. fabiana_nabarro@hotmail.com AbstractOBJECTIVE:To evaluate the effects of different forms of administration of the blood trypomastigotes biotherapy 7dH in mice experimentally infected with Trypanosoma cruzi. MATERIAL AND METHODS:Male swiss mice were inoculated with 1400 blood trypomastigotes of the Y strain of T. cruzi and allocated into 5 treatment groups: IC (distilled water); TCBZ (benznidazole); TBA(7dH) (biotherapy 7dH 20 days after infection); TBB(7dH)7 (biotherapy 7dH seven days before infection); TBB(7dH)30 (biotherapy 7dH 30 days before infection). Parasitological parameters assessed included pre-patent and patent periods, parasitemia peak, total parasitemia, mortality and survival rates. Cure index was obtained by fresh blood examination, hemoculture and polymerase chain reaction (PCR). RESULTS:The TBB(7dH)7 group showed a reduction in parasitemia peak, parasitemia area under the curve and total parasitemia. TBB(7dH)30 showed a tendency to increased pre-patent and survival periods, peak parasitemia was increased without increased total parasitemia. TBA(7dH) did not present significant alterations in the parasitological parameters analyzed. CONCLUSIONS:Biotherapy 7dH given before infection (7 or 30 days) produces different effects suggesting modulation of the host's immune system. The effects range from reduced parasitemia to its effective increase. The use of biotherapy to treat T. cruzi infection including dose, potency and schedule deserves further investigation. Copyright © 2011 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved. |
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| 8. | Int J Epidemiol. 2011 Aug;40(4):862-7. Epub 2010 Aug 30.Cohort profile: the Bambui (Brazil) Cohort Study of Ageing.Lima-Costa MF, Firmo JO, Uchoa E.SourceInstituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Brazil. lima-costa@cpqrr.fiocruz.br |
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