What's new for 'Trypanosomatids' in PubMed

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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 - 10 of 29

1.	Indian J Pediatr. 2011 Jan 4. [Epub ahead of print] Splenic Lesions in Visceral Leishmaniasis. Saxena AK, Sodhi KS, Narayanan S, Singhi S, Khandelwal N. Department of Radiodiagnosis, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India.
	PMID: 21203867 [PubMed - as supplied by publisher]

2.	PLoS One. 2010 Dec 21;5(12):e15566. Phosphorylation-Dependent Protein Interaction with Trypanosoma brucei 14-3-3 Proteins that Display Atypical Target Recognition. Inoue M, Yasuda K, Uemura H, Yasaka N, Inoue H, Sei Y, Horikoshi N, Fukuma T. Division of Eukaryotic Microbiology, Department of Infectious Medicine, Kurume University School of Medicine, Kurume, Japan. Abstract BACKGROUND: The 14-3-3 proteins are structurally conserved throughout eukaryotes and participate in protein kinase signaling. All 14-3-3 proteins are known to bind to evolutionally conserved phosphoserine-containing motifs (modes 1 and/or 2) with high affinity. In Trypanosoma brucei, 14-3-3I and II play pivotal roles in motility, cytokinesis and the cell cycle. However, none of the T. brucei 14-3-3 binding proteins have previously been documented. METHODOLOGY/PRINCIPAL FINDINGS: Initially we showed that T. brucei 14-3-3 proteins exhibit far lower affinity to those peptides containing RSxpSxP (mode 1) and RxY/FxpSxP (mode 2) (where x is any amino acid residue and pS is phosphoserine) than human 14-3-3 proteins, demonstrating the atypical target recognition by T. brucei 14-3-3 proteins. We found that the putative T. brucei protein phosphatase 2C (PP2c) binds to T. brucei 14-3-3 proteins utilizing its mode 3 motif (-pS/pTx(1-2)-COOH, where x is not Pro). We constructed eight chimeric PP2c proteins replacing its authentic mode 3 motif with potential mode 3 sequences found in Trypanosoma brucei genome database, and tested their binding. As a result, T. brucei 14-3-3 proteins interacted with three out of eight chimeric proteins including two with high affinity. Importantly, T. brucei 14-3-3 proteins co-immunoprecipitated with an uncharacterized full-length protein containing identified high-affinity mode 3 motif, suggesting that both proteins form a complex in vivo. In addition, a synthetic peptide derived from this mode 3 motif binds to T. brucei 14-3-3 proteins with high affinity. CONCLUSION/SIGNIFICANCE: Because of the atypical target recognition of T. brucei 14-3-3 proteins, no 14-3-3-binding proteins have been successfully identified in T. brucei until now whereas over 200 human 14-3-3-binding proteins have been identified. This report describes the first discovery of the T. brucei 14-3-3-binding proteins and their binding motifs. The high-affinity phosphopeptide will be a powerful tool to identify novel T. brucei 14-3-3-binding proteins.
	PMID: 21203569 [PubMed - in process]

3.	PLoS One. 2010 Dec 21;5(12):e14388. Towards the Construction of Expressed Proteomes Using a Leishmania tarentolae Based Cell-Free Expression System. Kovtun O, Mureev S, Johnston W, Alexandrov K. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. Abstract The adaptation of organisms to a parasitic life style is often accompanied by the emergence of novel biochemical pathways absent in free-living organisms. As a result, the genomes of specialized parasitic organisms often code for a large number (>50%) of proteins with no detectable homology or predictable function. Although understanding the biochemical properties of these proteins and their roles in parasite biogenesis is the next challenge of molecular parasitology, analysis tools developed for free-living organisms are often inadequate for this purpose. Here we attempt to solve some of these problems by developing a methodology for the rapid production of expressed proteomes in cell-free systems based on parasitic organisms. To do so we take advantage of Species Independent Translational Sequences (SITS), which can efficiently mediate translation initiation in any organism. Using these sequences we developed a single-tube in vitro translation system based on the parasitic protozoan Leishmania tarentolae. We demonstrate that the system can be primed directly with SITS containing templates constructed by overlap extension PCR. To test the systems we simultaneously amplified 31 of L. tarentolae's putative translation initiation factors and phosphatases directly from the genomic DNA and subjected them to expression, purification and activity analysis. All of the amplified products produced soluble recombinant proteins, and putative phosphatases could be purified to at least 50% purity in one step. We further compared the ability of L. tarentolae and E. coli based cell-free systems to express a set of mammalian, L. tarentolae and Plasmodium falciparum Rab GTPases in functional form. We demonstrate that the L. tarentolae cell-free system consistently produced higher quality proteins than E. coli-based system. The differences were particularly pronounced in the case of open reading frames derived from P. falciparum. The implications of these developments are discussed.
	PMID: 21203562 [PubMed - in process]

4.	PLoS One. 2010 Dec 22;5(12):e15577. TbUNC119 and Its Binding Protein Complex Are Essential for Propagation, Motility, and Morphogenesis of Trypanosoma brucei Procyclic Form Cells. Ohshima S, Ohashi-Suzuki M, Miura Y, Yabu Y, Okada N, Ohta N, Suzuki T. Department of Core Laboratory, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. Abstract Flagellum-mediated motility of Trypanosoma brucei is considered to be essential for the parasite to complete stage development in the tsetse fly vector, while the mechanism by which flagellum-mediated motility is controlled are not fully understood. We thus compared T. brucei whole gene products (amino acid sequence) with Caenorhabditis elegans UNC (uncoordinated) proteins, in order to find uncharacterized motility-related T. brucei genes. Through in silico analysis, we found 88 gene products which were highly similar to C. elegans UNC proteins and categorized them as TbCEUN (T. brucei gene products which have high similarity to C. elegansUNC proteins). Approximately two thirds of the 88 TbCEUN gene products were kinesin-related molecules. A gene product highly similar to C. elegans UNC119 protein was designated as TbUNC119. RNAi-mediated depletion of TbUNC119 showed no apparent phenotype. However, knock-down analysis of both TbUNC119 and its binding protein (TbUNC119BP) which was found by yeast two-hybrid analysis showed characteristic phenotypes, including reduced motility, morphological change (extended cell shape), and cellular apoptosis. Based on the observed phenotypes, possible function of the TbUNC119 and TbUNC119BP is discussed.
	PMID: 21203515 [PubMed - in process]

5.	PLoS Pathog. 2010 Dec 23;6(12):e1001245. Evidence That Intracellular Stages of Leishmania major Utilize Amino Sugars as a Major Carbon Source. Naderer T, Heng J, McConville MJ. The Department of Biochemistry and Molecular Biology, University of Melbourne, Bio21 Institute of Molecular Science and Biotechnology, Parkville, Victoria, Australia. Abstract Intracellular parasites, such as Leishmania spp, must acquire suitable carbon sources from the host cell in order to replicate. Here we present evidence that intracellular amastigote stages of Leishmania exploit amino sugars in the phagolysosome of mammalian macrophages as a source of carbon and energy. L. major parasites are capable of using N-acetylglucosamine and glucosamine as primarily carbon sources and contain key enzymes required for conversion of these sugars to fructose-6-phosphate. The last step in this pathway is catalyzed by glucosamine-6-phosphate deaminase (GND), which was targeted to glycosomes via a canonical C-terminal targeting signal when expressed as a GFP fusion protein. Mutant parasites lacking GND were unable to grow in medium containing amino sugars as sole carbohydrate source and rapidly lost viability, concomitant with the hyper-accumulation of hexosamine-phosphates. Expression of native GND, but not a cytosolic form of GND, in Δgnd parasites restored hexosamine-dependent growth, indicating that toxicity is due to depletion of glycosomal pools of ATP. Non-lethal increases in hexosamine phosphate levels in both Δgnd and wild type parasites was associated with a defect in promastigote metacyclogenesis, suggesting that hexosamine phosphate levels may influence parasite differentiation. Promastigote and amastigote stages of the Δgnd mutant were unable to replicate within macrophages and were either completely cleared or exhibited reduced lesion development in highly susceptible Balb/c mice. Our results suggest that hexosamines are a major class of sugars in the macrophage phagolysosome and that catabolism of scavenged amino sugars is required to sustain essential metabolic pathways and prevent hexosamine toxicity.
	PMID: 21203480 [PubMed - in process]

6.	PLoS One. 2010 Dec 21;5(12):e14394. DET C Induces Leishmania Parasite Killing in Human In Vitro and Murine In Vivo Models: A Promising Therapeutic Alternative in Leishmaniasis. Khouri R, Novais F, Santana G, de Oliveira CI, Vannier Dos Santos MA, Barral A, Barral-Netto M, Van Weyenbergh J. LIMI, LIP, LBP, Centro de Pesquisa Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador-Bahia, Brazil. Abstract BACKGROUND: Chemotherapy remains the primary tool for treatment and control of human leishmaniasis. However, currently available drugs present serious problems regarding side-effects, variable efficacy, and cost. Affordable and less toxic drugs are urgently needed for leishmaniasis. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate, by microscopy and viability assays, that superoxide dismutase inhibitor diethyldithiocarbamate (DETC) dose-dependently induces parasite killing (p<0.001) and is able to "sterilize" Leishmania amazonensis infection at 2 mM in human macrophages in vitro. We also show that DETC-induced superoxide production (p<0.001) and parasite destruction (p<0.05) were reverted by the addition of the antioxidant N-acetylcysteine, indicating that DETC-induced killing occurs through oxidative damage. Furthermore, ultrastructural analysis by electron microscopy demonstrates a rapid and highly selective destruction of amastigotes in the phagosome upon DETC treatment, without any apparent damage to the host cell, including its mitochondria. In addition, DETC significantly induced parasite killing in Leishmania promastigotes in axenic culture. In murine macrophages infected with Leishmania braziliensis, DETC significantly induced in vitro superoxide production (p = 0.0049) and parasite killing (p = 0.0043). In vivo treatment with DETC in BALB/C mice infected with Leishmania braziliensis caused a significant decrease in lesion size (p<0.0001), paralleled by a 100-fold decrease (p = 0.0087) in parasite burden. CONCLUSIONS/SIGNIFICANCE: Due to its strong leishmanicidal effect in human macrophages in vitro, its in vivo effectiveness in a murine model, and its previously demonstrated in vivo safety profile in HIV treatment, DETC treatment might be considered as a valuable therapeutic option in human leishmaniasis, including HIV/Leishmania co-infection.
	PMID: 21200432 [PubMed - in process]

7.	PLoS Negl Trop Dis. 2010 Dec 21;4(12):e914. Bayesian geostatistical analysis and prediction of rhodesian human african trypanosomiasis. Wardrop NA, Atkinson PM, Gething PW, Fèvre EM, Picozzi K, Kakembo AS, Welburn SC. Centre for Infectious Diseases, Division of Pathway Medicine, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom. Abstract BACKGROUND: The persistent spread of Rhodesian human African trypanosomiasis (HAT) in Uganda in recent years has increased concerns of a potential overlap with the Gambian form of the disease. Recent research has aimed to increase the evidence base for targeting control measures by focusing on the environmental and climatic factors that control the spatial distribution of the disease. OBJECTIVES: One recent study used simple logistic regression methods to explore the relationship between prevalence of Rhodesian HAT and several social, environmental and climatic variables in two of the most recently affected districts of Uganda, and suggested the disease had spread into the study area due to the movement of infected, untreated livestock. Here we extend this study to account for spatial autocorrelation, incorporate uncertainty in input data and model parameters and undertake predictive mapping for risk of high HAT prevalence in future. MATERIALS AND METHODS: Using a spatial analysis in which a generalised linear geostatistical model is used in a Bayesian framework to account explicitly for spatial autocorrelation and incorporate uncertainty in input data and model parameters we are able to demonstrate a more rigorous analytical approach, potentially resulting in more accurate parameter and significance estimates and increased predictive accuracy, thereby allowing an assessment of the validity of the livestock movement hypothesis given more robust parameter estimation and appropriate assessment of covariate effects. RESULTS: Analysis strongly supports the theory that Rhodesian HAT was imported to the study area via the movement of untreated, infected livestock from endemic areas. The confounding effect of health care accessibility on the spatial distribution of Rhodesian HAT and the linkages between the disease's distribution and minimum land surface temperature have also been confirmed via the application of these methods. CONCLUSIONS: Predictive mapping indicates an increased risk of high HAT prevalence in the future in areas surrounding livestock markets, demonstrating the importance of livestock trading for continuing disease spread. Adherence to government policy to treat livestock at the point of sale is essential to prevent the spread of sleeping sickness in Uganda.
	PMID: 21200429 [PubMed - in process]

8.	PLoS Negl Trop Dis. 2010 Dec 21;4(12):e923. Fexinidazole - a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. Torreele E, Bourdin Trunz B, Tweats D, Kaiser M, Brun R, Mazué G, Bray MA, Pécoul B. Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland. Abstract BACKGROUND: Human African trypanosomiasis (HAT), also known as sleeping sickness, is a fatal parasitic disease caused by trypanosomes. Current treatment options for HAT are scarce, toxic, no longer effective, or very difficult to administer, in particular for the advanced, fatal stage of the disease (stage 2, chronic HAT). New safe, effective and easy-to-use treatments are urgently needed. Here it is shown that fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining efforts of more than 700 new and existing nitroheterocycles, could be a short-course, safe and effective oral treatment curing both acute and chronic HAT and that could be implemented at the primary health care level. To complete the preclinical development and meet the regulatory requirements before initiating human trials, the anti-parasitic properties and the pharmacokinetic, metabolic and toxicological profile of fexinidazole have been assessed. METHODS AND FINDINGS: Standard in vitro and in vivo anti-parasitic activity assays were conducted to assess drug efficacy in experimental models for HAT. In parallel, a full range of preclinical pharmacology and safety studies, as required by international regulatory guidelines before initiating human studies, have been conducted. Fexinidazole is moderately active in vitro against African trypanosomes (IC(50) against laboratory strains and recent clinical isolates ranged between 0.16 and 0.93 µg/mL) and oral administration of fexinidazole at doses of 100 mg/kg/day for 4 days or 200 mg/kg/day for 5 days cured mice with acute and chronic infection respectively, the latter being a model for the advanced and fatal stage of the disease when parasites have disseminated into the brain. In laboratory animals, fexinidazole is well absorbed after oral administration and readily distributes throughout the body, including the brain. The absolute bioavailability of oral fexinidazole was 41% in mice, 30% in rats, and 10% in dogs. Furthermore, fexinidazole is rapidly metabolised in vivo to at least two biologically active metabolites (a sulfoxide and a sulfone derivative) that likely account for a significant portion of the therapeutic effect. Key pharmacokinetic parameter after oral absorption in mice for fexinidazole and its sulfoxide and sulfone metabolites are a C(max) of 500, 14171 and 13651 ng/mL respectively, and an AUC(0-24) of 424, 45031 and 96286 h.ng/mL respectively. Essentially similar PK profiles were observed in rats and dogs. Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog) have shown that fexinidazole is well tolerated. The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day. While fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo as assessed in an in vitro micronucleus test on human lymphocytes, an in vivo mouse bone marrow micronucleus test, and an ex vivo unscheduled DNA synthesis test in rats. CONCLUSIONS: The results of the preclinical pharmacological and safety studies indicate that fexinidazole is a safe and effective oral drug candidate with no untoward effects that would preclude evaluation in man. The drug has entered first-in-human phase I studies in September 2009. Fexinidazole is the first new clinical drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years.
	PMID: 21200426 [PubMed - in process]

9.	PLoS Negl Trop Dis. 2010 Dec 21;4(12):e912. Miltefosine in the Treatment of Cutaneous Leishmaniasis Caused by Leishmania braziliensis in Brazil: A Randomized and Controlled Trial. Machado PR, Ampuero J, Guimarães LH, Villasboas L, Rocha AT, Schriefer A, Sousa RS, Talhari A, Penna G, Carvalho EM. Serviço de Imunologia, Hospital Universitário Prof. Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil. Abstract BACKGROUND: Cutaneous leishmaniasis (CL) is treated with parenteral drugs for decades with decreasing rate cures. Miltefosine is an oral medication with anti-leishmania activity and may increase the cure rates and improve compliance. METHODOLOGY/PRINCIPAL FINDINGS: This study is a randomized, open-label, controlled clinical trial aimed to evaluate the efficacy and safety of miltefosine versus pentavalent antimony (Sb(v)) in the treatment of patients with CL caused by Leishmania braziliensis in Bahia, Brazil. A total of 90 patients were enrolled in the trial; 60 were assigned to receive miltefosine and 30 to receive Sb(v). Six months after treatment, in the intention-to-treat analyses, the definitive cure rate was 53.3% in the Sb(v) group and 75% in the miltefosine group (difference of 21.7%, 95% CI 0.08% to 42.7%, p = 0.04). Miltefosine was more effective than Sb(v) in the age group of 13-65 years-old compared to 2-12 years-old group (78.9% versus 45% p = 0.02; 68.2% versus 70% p = 1.0, respectively). The incidence of adverse events was similar in the Sb(v) and miltefosine groups (76.7% vs. 78.3%). Vomiting (41.7%), nausea (40%), and abdominal pain (23.3%) were significantly more frequent in the miltefosine group while arthralgias (20.7%), mialgias (20.7%) and fever (23.3%) were significantly more frequent in the Sb(v) group. CONCLUSIONS: This study demonstrates that miltefosine therapy is more effective than standard Sb(v) and safe for the treatment of CL caused by Leishmania braziliensis in Bahia, Brazil. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT00600548.
	PMID: 21200420 [PubMed - in process]

10.	PLoS Negl Trop Dis. 2010 Dec 21;4(12):e917. Revisiting the immune trypanolysis test to optimise epidemiological surveillance and control of sleeping sickness in west Africa. Jamonneau V, Bucheton B, Kaboré J, Ilboudo H, Camara O, Courtin F, Solano P, Kaba D, Kambire R, Lingue K, Camara M, Baelmans R, Lejon V, Büscher P. Institut de Recherche pour le Développement (IRD), Unité Mixte de Recherche IRD-CIRAD 177, Montpellier, France. Abstract BACKGROUND: Because of its high sensitivity and its ease of use in the field, the card agglutination test for trypanosomiasis (CATT) is widely used for mass screening of sleeping sickness. However, the CATT exhibits false-positive results (i) raising the question of whether CATT-positive subjects who are negative in parasitology are truly exposed to infection and (ii) making it difficult to evaluate whether Trypanosoma brucei (T.b.) gambiense is still circulating in areas of low endemicity. The objective of this study was to assess the value of the immune trypanolysis test (TL) in characterising the HAT status of CATT-positive subjects and to monitor HAT elimination in West Africa. METHODOLOGY/PRINCIPAL FINDINGS: TL was performed on plasma collected from CATT-positive persons identified within medical surveys in several West African HAT foci in Guinea, Côte d'Ivoire and Burkina Faso with diverse epidemiological statuses (active, latent, or historical). All HAT cases were TL+. All subjects living in a nonendemic area were TL-. CATT prevalence was not correlated with HAT prevalence in the study areas, whereas a significant correlation was found using TL. CONCLUSION AND SIGNIFICANCE: TL appears to be a marker for contact with T.b. gambiense. TL can be a tool (i) at an individual level to identify nonparasitologically confirmed CATT-positive subjects as well as those who had contact with T.b. gambiense and should be followed up, (ii) at a population level to identify priority areas for intervention, and (iii) in the context of HAT elimination to identify areas free of HAT.
	PMID: 21200417 [PubMed - in process]