What's new for 'Trypanosomatids' in PubMed

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Sent on Wednesday, 2010 Aug 04
Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results

Items 1 - 9 of 9

1.	Parasitol Res. 2010 Aug 3. [Epub ahead of print] Development and laboratory evaluation of a lateral flow device (LFD) for the serodiagnosis of Theileria annulata infection. Abdo J, Kristersson T, Seitzer U, Renneker S, Merza M, Ahmed J. Division of Veterinary Infection Biology and Immunology, Research Center Borstel, Parkallee 22, 23845, Borstel, Germany. Abstract Several DNA-based and serological tests have been established for the detection of Theileria annulata infection, including polymerase chain reaction, reverse line blot and loop-mediated isothermal amplification, indirect enzyme-linked immunosorbent assay (ELISA), and competitive ELISA. In this study, we have applied knowledge from the development and application of a recombinant protein-based indirect ELISA and competitive ELISA to establish a rapid test for point-of-care diagnosis of T. annulata infection in the field to be used by the veterinarian. For the development of a lateral flow test, the recombinantly expressed T. annulata surface protein (TaSP) was applied as the test antigen and anti-TaSP antiserum as the control line. TaSP antigen conjugated to colloidal gold particles was used as the detection system for visualization at the test line for the binding of anti-TaSP antibody present in the serum of infected animals. The developed test specifically detected antibodies in the serum of animals experimentally infected with T. annulata and showed no cross-reactivity with serum from animals infected with other tested bovine pathogens (Trypanosoma brucei, Anaplasma marginale, Babesia bigemina, Babesia bovis, and Theileria parva). Testing of field samples was compared to results obtained by other serological tests, resulting in a sensitivity and specificity of 96.3% and 87.5% compared to indirect fluorescence antibody test, 98.7% and 81.8% compared to indirect ELISA, and 100% and 47.6% compared to competitive ELISA. In conclusion, a rapid test for the detection of T. annulata infection (T. annulata lateral flow device, Ta-LFD) has been developed, which is easy to perform, delivers results to be read by the naked eye within 10 min, and is suitable for the detection of infection in field samples.
	PMID: 20680339 [PubMed - as supplied by publisher]

2.	Antimicrob Agents Chemother. 2010 Aug 2. [Epub ahead of print] Trypanocidal activity of aziridinyl nitrobenzamide prodrugs. Bot C, Hall BS, Bashir N, Taylor MC, Helsby NA, Wilkinson SR. Queen Mary Pre-Clinical Drug Discovery Group, School of Biological and Chemical Sciences, Queen Mary University of London, London, E1 4NS, UK; Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK; Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland, New Zealand. Abstract The trypanocidal agents nifurtimox and benznidazole both function as prodrugs and must undergo enzyme-mediated activation, a reaction catalysed by type I nitroreductase (NTR). In the search for new parasitic therapies, we have utilized this finding to investigate whether aziridinyl nitrobenzamide derivatives have activity against bloodstream form Trypanosoma brucei and Trypanosoma cruzi amastigotes, parasite stages that replicate in the mammalian host. For T. cruzi drug screening, we generated trypanosomes that expressed the luciferase reporter gene and optimised a mammalian infection model in a 96 well plate format. A sub-set of compounds having a 5-(aziridin-1-yl)-2,4-dinitrobenzyl structure, were shown to be metabolised by purified T. brucei NTR and when screened against both parasite life cycle stages displayed significant growth inhibitory properties: the most potent compounds generated IC50 values of <1 muM. The trypanocidal activity was shown to be NTR specific as parasites overexpressing this enzyme were hypersensitive to the aziridinyl dinitrobenzyl agents. We conclude that members of the aziridinyl nitrobenzamide class of nitroheterocycles provide new lead structures that have potential to treat trypanosomal infections.
	PMID: 20679506 [PubMed - as supplied by publisher]

3.	Biochimie. 2010 Jul 30. [Epub ahead of print] The effect of C-terminal domain deletion on the catalytic activity of Leishmania donovani surface proteinase GP63: Role of Ser 446 in proteolysis. Mazumder S, Ganguly A, Ali N. Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata-700032, India. Abstract The kinetoplastid protozoan Leishmania encodes major surface glycoprotein GP63, a zinc metallo-peptidase (EC.3.4.24.36) expressed both in promastigote and amastigote life stages. In the present study, we explored for the first time the role of C-terminal domain (CTD) in proteinase activity by serial truncation of Leishmania donovani GP63 (LdGP63) from carboxyl terminal end (CTend). Deletion of 180-211 amino acids from CTend (Delta420 and Delta389) resulted in almost 50% loss of catalytic activity against azocasein, casein and gelatin. Moreover, all the truncated constructs showed reduced activity towards immunoglobulin (IgG). Upon homology modeling, we identified two residues, S446, and F448 in CTD, conserved in different Leishmania species, which were positioned 6.8-11 A apart from the active site. To ascertain the role of S446 and F448 in catalysis, we replaced S446 with Ala and Thr, and F448 with Val and Tyr by site-directed mutagenesis. The variant enzymes (S446T, F448V, and F448Y) maintained near wild-type activity, whereas S446A demonstrated 50% loss of catalytic activity towards the cleavage of various biological substrates. Kinetic analysis of S446A resulted in a 2.6 fold decrease in the affinity, 10 fold decrease in turn-over rates, and large increase in transition state binding energy (1.4 kcal/mol) for the quenched peptide substrates. These results emphasize the relevance of CTD in the proteolytic activity of LdGP63. Fluorescence spectroscopy, and CD analysis however, indicated that the reduced activities showed by Delta389 and S446A were not due to global changes in the enzyme structures. Indeed, identification of S446 and its possible role in the stabilization of transition state binding between enzyme and substrate can be exploited towards understanding of structure-function relationship of GP63. Copyright © 2010. Published by Elsevier Masson SAS.
	PMID: 20678540 [PubMed - as supplied by publisher]

4.	Biochem Biophys Res Commun. 2010 Jul 30. [Epub ahead of print] Amphotericin B Inhibits Entry of Leishmania donovani into Primary Macrophages. Paila YD, Saha B, Chattopadhyay A. Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Uppal Road, Hyderabad 500 007, India. Abstract Visceral leishmaniasis is a vector-borne disease caused by an obligate intra-macrophage protozoan parasite Leishmania donovani. The molecular mechanisms involved in internalization of Leishmania are still poorly understood. Amphotericin B and its formulations are considered as the best existing drugs against visceral leishmaniasis and are being increasingly used. The reason for its antileishmanial activity is believed to be its ability to bind ergosterol found in parasite membranes. In case of in vivo amphotericin B treatment, both host macrophages and parasites are exposed to amphotericin B. The effect of amphotericin B treatment could therefore be due to a combination of its interaction with both sterols i.e., ergosterol of Leishmania and cholesterol of host macrophages. We report here that cholesterol complexation by amphotericin B markedly inhibits binding of L. donovani promastigotes to macrophages. These results represent one of the first reports on the effect of amphotericin B on the binding of Leishmania parasites to host macrophages. Importantly, these results offer the possibility of reevaluating the mechanism behind the effectiveness of current therapeutic strategies that employ sterol-complexing agents such as amphotericin B to treat leishmaniasis. Copyright © 2010. Published by Elsevier Inc.
	PMID: 20678487 [PubMed - as supplied by publisher]

5.	Parasitology. 2010 Aug 3:1-11. [Epub ahead of print] Comparison of gene expression patterns among Leishmania braziliensis clinical isolates showing a different in vitro susceptibility to pentavalent antimony. Adaui V, Schnorbusch K, Zimic M, Gutiérrez A, Decuypere S, Vanaerschot M, DE Doncker S, Maes I, Llanos-Cuentas A, Chappuis F, Arévalo J, Dujardin JC. Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru. Abstract SUMMARYIntroduction. Evaluation of Leishmania drug susceptibility depends on in vitro SbV susceptibility assays, which are labour-intensive and may give a biased view of the true parasite resistance. Molecular markers are urgently needed to improve and simplify the monitoring of SbV-resistance. We analysed here the gene expression profile of 21 L. braziliensis clinical isolates in vitro defined as SbV-resistant and -sensitive, in order to identify potential resistance markers. Methods. The differential expression of 13 genes involved in SbV metabolism, oxidative stress or housekeeping functions was analysed during in vitro promastigote growth. Results. Expression profiles were up-regulated for 5 genes only, each time affecting a different set of isolates (mosaic picture of gene expression). Two genes, ODC (ornithine decarboxylase) and TRYR (trypanothione reductase), showed a significantly higher expression rate in the group of SbV-resistant compared to the group of SbV-sensitive parasites (P<0.01). However, analysis of individual isolates showed both markers to explain only partially the drug resistance. Discussion. Our results might be explained by (i) the occurrence of a pleiotropic molecular mechanism leading to the in vitro SbV resistance and/or (ii) the existence of different epi-phenotypes not revealed by the in vitro SbV susceptibility assays, but interfering with the gene expression patterns.
	PMID: 20678296 [PubMed - as supplied by publisher]

6.	BMC Genomics. 2010 Aug 2;11(1):457. [Epub ahead of print] A new family of phosphoinositide phosphatases in microorganisms: identification and biochemical analysis. Beresford NJ, Saville C, Bennett HJ, Roberts IS, Tabernero L. Abstract ABSTRACT: BACKGROUND: Phosphoinositide metabolism is essential to membrane dynamics and impinges on many cellular processes, including phagocytosis. Modulation of phosphoinositide metabolism is important for pathogenicity and virulence of many human pathogens, allowing them to survive and replicate in the host cells. Phosphoinositide phosphatases from bacterial pathogens are therefore key players in this modulation and constitute attractive targets for chemotherapy. MptpB, a virulence factor from Mycobacterium tuberculosis, has phosphoinositide phosphatase activity and a distinct active site P-loop signature HCXXGKDR that shares characteristics with eukaryotic lipid phosphatases and protein tyrosine phosphatases. We used this P-loop signature as a "diagnostic motif" to identify related putative phosphatases with phosphoinositide activity in other organisms. RESULTS: We found more than 200 uncharacterised putative phosphatase sequences with the conserved signature in bacteria, with some related examples in fungi and protozoa. Many of the sequences identified belong to recognised human pathogens. Interestingly, no homologues were found in any other organisms including Archaea, plants, or animals. Phylogenetic analysis revealed that these proteins are unrelated to classic eukaryotic lipid phosphatases. However, biochemical characterisation of those from Listeria monocytogenes and Leishmania major, demonstrated that, like MptpB, they have phosphatase activity towards phosphoinositides. Mutagenesis studies established that the conserved Asp and Lys in the P-loop signature (HCXXGKDR) are important in catalysis and substrate binding respectively. Furthermore, we provide experimental evidence that the number of basic residues in the P-loop is critical in determining activity towards poly-phosphoinositides. CONCLUSION: This new family of enzymes in microorganisms shows distinct sequence and biochemical characteristics to classic eukaryotic lipid phosphatases and they have no homologues in humans. This study provides a foundation for examining the biological role of this new family of phosphatases and their potential as pharmaceutical targets against infectious diseases.
	PMID: 20678187 [PubMed - as supplied by publisher]

7.	Ann Diagn Pathol. 2010 Jun;14(3):199-203. Epub 2009 Oct 31. Acute Chagas' disease in postrenal transplant and treatment with benzonidazole. Silva AE, Silva AC, Faleiros AC, Guimarães CS, Corrêa RR, Oliveira FA, Correia D, Teixeira AC, Ramirez LE, Teixeira Vde P, dos Reis MA. Discipline of General Pathology, Triângulo Mineiro Federal University, Uberaba, the State of Minas Gerais, Brazil. Abstract Transplanted organs may act as a route of transmission of infectious diseases, such as Chagas' disease. The aim of this study was to describe the transmission of the Trypanosoma cruzi through a renal transplant and the anatomo-clinical evolution of the patient after treatment with benzonidazole. The patient was a 31-year-old white male from the State of Minas Gerais in Brazil. He had renal failure secondary to diabetes and later received a kidney from a cadaveric donor. The patient was undergoing immunosuppression therapy with azathioprine, cyclosporine A, and prednisone. After the transplant, he developed an acute phase of Chagas' disease and complications from diabetes and died 2 months later. In the autopsy, T cruzi amastigotes were found in the transplanted kidney, heart, bladder, liver, and pancreas. An important reduction in the parasitemia was obtained through the treatment of the infection with benzonidazole; however, the patient died due to complications from diabetes associated with tissue lesions caused by T cruzi.
	PMID: 20471566 [PubMed - indexed for MEDLINE]
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8.	Int J Dermatol. 2009 Dec;48(12):1275-82; quiz 1282. Granulomatous diseases of the nose. Zargari O, Elpern DJ. Pars Clinic, Rasht, Iran. ozargari@iranderma.com
	PMID: 20415668 [PubMed - indexed for MEDLINE]
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9.	Biosystems. 2010 Jun;100(3):225-30. Epub 2010 Mar 25. A three-dimensional multi-agent-based model for the evolution of Chagas' disease. Galvão V, Miranda JG. Departamento de Ciências Biológicas, Universidade Estadual de Feira de Santana, Feira de Santana, BA, Brazil. vivianegalvao@uefs.br Abstract A better understanding of Chagas' disease is important because the knowledge about the progression and the participation of the different types of cells in this disease are still lacking. To clarify this system, the kinetics of inflammatory cells and parasite nests was shown in an experiment. Using this experimental data, we have developed a three-dimensional multi-agent-based computational model for the evolution of Chagas' disease. Our model includes five different types of agents: inflammatory cell, fibrosis, cardiomyocyte, fibroblast, and Trypanosoma cruzi. Fibrosis is fixed and the other types of agents can move through the empty space. They move randomly by using the Moore neighborhood. This model reproduces the acute and chronic phases of Chagas' disease and the volume occupied by all different types of cells in the cardiac tissue.
	PMID: 20347006 [PubMed - indexed for MEDLINE]
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