What's new for 'Trypanosomatids' in PubMed

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Sent on Tuesday, 2011 Jan 25
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 14

1.	Eukaryot Cell. 2011 Jan 21. [Epub ahead of print] A Second Mitochondrial DNA Primase is Essential for Cell Growth and Kinetoplast Minicircle DNA Replication in Trypanosoma brucei. Hines JC, Ray DS. Molecular Biology Institute and Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA 90095-1570. Abstract The mitochondrial DNA of trypanosomes contains two types of circular DNAs, minicircles and maxicircles. Both minicircles and maxicircles replicate from specific replication origins by unidirectional theta-type intermediates. Initiation of the minicircle leading strand and also that of at least the first Okazaki fragment involve RNA priming. The T. brucei genome encodes two mitochondrial DNA primases, PRI1 and PRI2, related to the primases of eukaryotic nucleo-cytoplasmic large DNA viruses. These primases are members of the archeo-eukaryotic primase superfamily and both contain an RNA recognition motif and a PriCT-2 motif. In Leishmania species PRI2 proteins are approximately 61 to 66 kDa whereas in Trypanosoma species PRI2 proteins have additional long amino terminal extensions. RNA interference (RNAi) of T. brucei PRI2 resulted in the loss of kinetoplast DNA and accumulation of covalently closed free minicircles. Recombinant PRI2 lacking this extension (PRI2ΔNT) primes poly (dA) synthesis on a poly (dT) template in an ATP dependent manner. Mutation of two conserved aspartate residues (PRI2ΔNTCS) resulted in loss of enzymatic activity but not of DNA binding. We propose that PRI2 is directly involved in initiating kinetoplast minicircle replication.
	PMID: 21257796 [PubMed - as supplied by publisher]
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2.	Exp Parasitol. 2011 Jan 19. [Epub ahead of print] Trypanosoma brucei brucei: Endocytic recycling is important for mouse infectivity. Natesan SK, Black A, Matthews KR, Mottram JC, Field MC. Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge CB2 1QP, UK. Abstract Endocytosis in the African trypanosome, Trypanosoma brucei, is intimately involved in maintaining homeostasis of the cell surface proteome, morphology of the flagellar pocket and has recently been demonstrated as a bona fide drug target. RNAi-mediated knockdown of many factors required for endocytic transport, including several small GTPases, the major coat protein clathrin and a clathrin-associated receptor, epsinR, results in rapid cell death in vitro. Rapid loss of viability in vitro precludes meaningful investigation by RNAi of the roles of trypanosome endocytosis in vivo. Here we have sought to address this issue using strategies designed to produce milder effects on the endocytic system than complete functional ablation. We created a trypanosome clathrin heavy chain hemizygote and several lines expressing mutant forms of Rab5 and Rab11, described previously. All are viable in in vitro culture, with negligible impact to proliferative rates or cell cycle. Clathrin hemizygotes express clathrin heavy chain at ∼50% of wild type levels, but despite this demonstrate no defect to growth in mice, while none of the Rab5 mutants affected proliferation in vivo, despite clear evidence for effects on endocytosis. By contrast we find that expressing a dominantly active Rab11 mutant led to compromised growth in mice. These data indicate that trypanosomes likely tolerate the effects of partly decreased clathrin expression and alterations in early endocytosis, but are more sensitive to alterations in the recycling arm of the pathway. Copyright © 2011 Elsevier Inc. All rights reserved.
	PMID: 21256128 [PubMed - as supplied by publisher]
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3.	Lancet. 2011 Jan 19. [Epub ahead of print] Combination therapy for visceral leishmaniasis. van Griensven J, Boelaert M. Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp 2000, Belgium.
	PMID: 21255829 [PubMed - as supplied by publisher]
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4.	Lancet. 2011 Jan 19. [Epub ahead of print] Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. Sundar S, Sinha PK, Rai M, Verma DK, Nawin K, Alam S, Chakravarty J, Vaillant M, Verma N, Pandey K, Kumari P, Lal CS, Arora R, Sharma B, Ellis S, Strub-Wourgaft N, Balasegaram M, Olliaro P, Das P, Modabber F. Kala-Azar Medical Research Center, Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India. Abstract BACKGROUND: Improved treatment approaches are needed for visceral leishmaniasis. We assessed the efficacy and safety of three potential short-course combination treatments compared with the standard monotherapy in India. METHODS: Standard treatment (1 mg/kg amphotericin B infusion on alternate days for 30 days, total dose 15 mg/kg) was compared with three drug combinations (single injection of 5 mg/kg liposomal amphotericin B and 7-day 50 mg oral miltefosine or single 10-day 11 mg/kg intramuscular paromomycin; or 10 days each of miltefosine and paromomycin) in an open-label, parallel-group, non-inferiority, randomised controlled trial in two hospital sites in Bihar, India. Patients aged 5-60 years with parasitologically confirmed visceral leishmaniasis were randomly assigned one of the four treatments by the trial statistician by use of a computer-generated list. Clinical assessments were done at the end of treatment (15 days on combination treatment; 31 days for standard treatment) and after 45 days and 6 months. The primary endpoint was definitive cure (defined as no sign or symptom of visceral leishmaniasis and parasitologically cured to the last follow-up). Analyses were done both by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00696969. FINDINGS: Between June, 2008, and July, 2009, 634 patients were assigned amphotericin B (n=157), liposomal amphotericin B with miltefosine (n=160) or paromomycin (n=158), or miltefosine and paromomycin (n=159). 618 patients were in the per-protocol population. There were two relapses in each group. The numbers with definitive cure at 6 months for the intention-to-treat population were 146 (cure rate 93·0%; CI 87·5-96·3) for amphotericin B, 156 (97·5%; 93·3-99·2) for liposomal amphotericin B and miltefosine, 154 (97·5%; 93·24-99·2) for liposomal amphotericin B and paromomycin, and 157 (98·7%; 95·1-99·8) for miltefosine and paromomycin. All combinations were non-inferior to the standard treatment, in both the intention-to-treat and per-protocol populations. Patients in the combination groups had fewer adverse events than did those assigned standard treatment. INTERPRETATION: Combination treatments for visceral leishmaniasis are efficacious and safe, and decrease the duration of therapy, thereby encouraging adherence and reducing emergence of drug-resistant parasites. FUNDING: Drugs for Neglected Diseases initiative and the Indian Council of Medical Research. Copyright © 2011 Elsevier Ltd. All rights reserved.
	PMID: 21255828 [PubMed - as supplied by publisher]
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5.	Mol Biochem Parasitol. 2011 Jan 18. [Epub ahead of print] Crystal structures of three protozoan homologs of tryptophanyl-tRNA synthetase. Merritt EA, Arakaki TL, Gillespie R, Napuli AJ, Kim JE, Buckner FS, Van Voorhis WC, Verlinde CL, Fan E, Zucker F, Hol WG. Department of Biochemistry, University of Washington, Seattle, WA 98195 USA; Medical Structural Genomics of Pathogenic Protozoa, http://msgpp.org. Abstract Tryptophanyl-tRNA synthetase (TrpRS) is an essential enzyme that is recognizably conserved across all forms of life. It is responsible for activating and attaching tryptophan to a cognate tRNATrp molecule for use in protein synthesis. In some eukaryotes this original core function has been supplemented or modified through the addition of extra domains or the expression of variant TrpRS isoforms. The three TrpRS structures from pathogenic protozoa described here represent three illustrations of this malleability in eukaryotes. The Cryptosporidium parvum genome contains a single TrpRS gene, which codes for an N-terminal domain of uncertain function in addition to the conserved core TrpRS domains. Sequence analysis indicates that this extra domain, conserved among several apicomplexans, is related to the editing domain of some AlaRS and ThrRS. The C. parvum enzyme remains fully active in charging tRNATrp after truncation of this extra domain. The crystal structure of the active, truncated enzyme is presented here at 2.4 Šresolution. The Trypanosoma brucei genome contains separate cytosolic and mitochondrial isoforms of TrpRS that have diverged in their respective tRNA recognition domains. The crystal structure of the T. brucei cytosolic isoform is presented here at 2.8 Šresolution. The Entamoeba histolytica genome contains three sequences that appear to be TrpRS homologs. However one of these, whose structure is presented here at 3.0 Šresolution, has lost the active site motifs characteristic of the Class I aminoacyl-tRNA synthetase catalytic domain while retaining the conserved features of a fully formed tRNATrp recognition domain. The biological function of this variant E. histolytica TrpRS remains unknown, but, on the basis of a completely conserved tRNA recognition region and evidence for ATP but not tryptophan binding, it is tempting to speculate that it may perform an editing function. Together with a previously reported structure of an unusual TrpRS from Giardia, these protozoan structures broaden our perspective on the extent of structural variation found in eukaryotic TrpRS homologs. Copyright © 2011. Published by Elsevier B.V.
	PMID: 21255615 [PubMed - as supplied by publisher]
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6.	Trop Med Int Health. 2011 Jan 24. doi: 10.1111/j.1365-3156.2011.02729.x. [Epub ahead of print] Emergence of a new focus of anthroponotic cutaneous leishmania sis due to Leishmania tropica in rural communities of Bam district after the earthquake, Iran. Sharifi I, Poursmaelian S, Aflatoonian MR, Ardakani RF, Parizi MH, Mirzaei M, Fekri AR, Harandi MF, Khamesipour A.  Dermatology and Leishmaniasis Research Center, Kerman University of Medical Sciences, Kerman, Iran  Parasitology Unit, Department of Pathobiology, Faculty of Veterinary Medicine, Shahid Bahonar University, Kerman, Iran  Center for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran. Abstract Objectives  To describe a new emerging focus of anthroponotic cutaneous leishmaniasis (ACL) due to Leishmania tropica in rural areas of Dehbakry county, south-eastern Iran, after the earthquake of 2003. Methods  House-to-house survey of 3884 inhabitants for active leishmaniasis lesions or scars. The diagnosis was confirmed by smears, cultures and identification of the parasite by polymerase chain reaction (PCR). Results  All age groups were affected, although patients ≤10 years of age showed the highest rate of infection (P = 0.0001). The overall prevalence rate was 5.3%; 6.3% in females and 4.3% in males. Of 204 cases, 1.8% had active sores and 3.5% had scars, with a significant difference between the sexes (P = 0.005). 47% of the lesions were on the face and 77.9% had one lesion. The incidence rose gradually 2004-2005, but grew exponentially 2006-2008. Electrophoresis of PCR products indicated that L. tropica was the causative agent. Conclusions  The current emergence was unexpected in this rural locality, where no previous history of CL was recorded. According to our knowledge this is the first report of a gradually establishing new ACL focus in rural communities after the 2003 earthquake. © 2011 Blackwell Publishing Ltd.
	PMID: 21255206 [PubMed - as supplied by publisher]
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7.	Mol Microbiol. 2011 Jan 23. doi: 10.1111/j.1365-2958.2010.07531.x. [Epub ahead of print] A new ATP-binding c assette protein is involved in intracellular haem trafficking in Leishmania. Campos-Salinas J, Cabello-Donayre M, García-Hernández R, Pérez-Victoria I, Castanys S, Gamarro F, Pérez-Victoria JM. Instituto de Parasitología y Biomedicina 'López-Neyra', CSIC, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18100 Armilla, Granada, Spain. Abstract The characterization of LABCG5, a new intracellular ATP-binding cassette protein in Leishmania donovani, is described. Unlike other ABCG half-transporters, LABCG5 is not involved in either drug resistance or phospholipid efflux. However, we provide evidence suggesting that this protein is involved in intracellular haem trafficking. Thus, downregulation of LABCG5 function produced upon overexpression of an inactive version of the protein caused a dramatic growth arrest unless a haemin supplement was added or the mutated gene was eliminated. Supplementation with haemoglobin, an upstream metabolite normally sufficient to meet parasite haem requirements, was unable to rescue the growth defect phenotype. Haemoglobin endocytosis was not hampered in dominant-negative parasites and neither was haem uptake, a process that we show here to be dependent on a specific transporter. In contrast, LABCG5 function was required for the correct intracellular trafficking of haemoglobin-bound porphyrins to the mitochondria, not affecting the routing of free haem. Finally, LABCG5 binds haem through hydrophobic and electrostatic interactions. Altogether, these data suggest that LABCG5 is involved in the salvage of the haem released after the breakdown of internalized haemoglobin. As Leishmania is auxotrophic for haem, the pharmacological targeting of this route could represent a novel approach to control fatal visceral leishmaniasis. © 2011 Blackwell Publishing Ltd.
	PMID: 21255121 [PubMed - as supplied by publisher]
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8.	Mol Microbiol. 2011 Feb;79(3):647-62. doi: 10.1111/j.1365-2958.2010.07479.x. Epub 2010 Dec 13. The cell cycle of Leishmania: morphogenetic events and their implications for para site biology. Wheeler RJ, Gluenz E, Gull K. The Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. Abstract The cell cycle is central to understanding fundamental biology of Leishmania, a group of human-infective protozoan parasites. Leishmania have two main life cycle morphologies: the intracellular amastigote in the mammalian host and the promastigote in the fly. We have produced the first comprehensive and quantitative description of a Leishmania promastigote cell cycle taking a morphometric approach to position any cell within the cell cycle based on its length and DNA content. We describe timings of cell cycle phases and rates of morphological changes; kinetoplast and nucleus S phase, division and position, cell body growth and morphology changes, flagellum growth and basal body duplication. We have shown that Leishmania mexicana undergoes large changes in morphology through the cell cycle and that the wide range of morphologies present in cultures during exponential growth represent different cell cycle stages. We also show promastigote flagellum growth occurs over multiple cell cycles. There are clear implications for the mechanisms of flagellum length regulation, life cycle stage differentiation and trypanosomatid division in general. This data set therefore provides a platform which will be of use for post-genomic analyses of Leishmania cell biology in relation to differentiation and infection. © 2010 Blackwell Publishing Ltd.
	PMID: 21255109 [PubMed - in process]
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9.	Vector Borne Zoonotic Dis. 2011 Jan 22. [Epub ahead of print] First Surve ys to Investigate the Presence of Canine Leishmaniasis and Its Phlebotomine Vectors in Hungary. Farkas R, Tánczos B, Bongiorno G, Maroli M, Dereure J, Ready PD. 1 Department of Parasitology and Zoology, Faculty of Veterinary Science, Szent István University , Budapest, Hungary . Abstract Abstract Hungary is regarded as free of leishmaniasis because only a few imported cases have been reported. However, southern Hungary has a sub-Mediterranean climate, and so it was included in the EU FP6 EDEN project, which aimed to map the northern limits of canine leishmaniasis (CanL) in Europe. The numbers of traveling and imported dogs have increased in the last decade, raising concerns about the introduction of CanL caused by Leishmania infantum. Serum samples were collected from 725 dogs (22 localities, 6 counties) that had never traveled to endemic countries, as well as from other potential reservoir hosts (185 red foxes and 13 golden jackals). All sera were tested by the indirect fluorescent antibody test, but they were sero-negative using the OIE cut-off of 1:80 serum dilution except for those of two dogs resident since birth in southern Hungary. These had not received a blood transfusion, but the mode of transmission is unclear because no sandfly vectors were caught locally. From 2006 to 2009, phlebotomine sandflies were sampled in the summer months at 47 localities of 8 counties. They were trapped with castor-oil-impregnated sticky-paper, light, and CO(2)-baited traps. Small numbers of two vectors of Leishmania infantum were found. Phlebotomus neglectus occurred in three villages near to Croatia and one in north Hungary at latitude 47°N, and Phlebotomus perfiliewi perfiliewi was trapped at two sites in a southeastern county close to the sites where it was first found in 1931-1932. Our report provides baseline data for future investigations into the northward spread of CanL into Hungary, which we conclude has yet to occur.
	PMID: 21254904 [PubMed - as supplied by publisher]
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10.	Vector Borne Zoonotic Dis. 2011 Jan 22. [Epub ahead of print] Molecular Detection and Genetic Diversity of Leishmania donovani in Naturally Infected Phlebotomus chinensi from Southwestern China. Wei F, Shang L, Jin H, Lian H, Liu W, Li Z, Gao H, Liu Q. 1 Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary , Academy of Military Medical Sciences, Changchun, People's Republic of China . Abstract Abstract Zoonotic visceral leishmaniasis is an important vector-borne infectious disease in western China. In this study, an epidemiological study was carried out on the vector of zoonotic visceral leishmaniasis in rural areas from Sichuan Province, southwestern China. In the 1263 phlebotomine sandflies captured, 859 (68.01%) were females and 404 (31.99%) males, belonging to Phlebotomus chinensis (83.37%), Sergentomyia koloshanensis (6.57%), Sergentomyia squamirostris (4.04%), and Sergentomyia barraudi (6.02%), respectively. The average prevalence of Leishmania parasites in P. chinensis females was 1.98%, which was detected by real-time quantitative PCR. Phylogenetic analysis based on ITS2-rDNA revealed that Leishmania parasites detected in sandflies belonged to the L. donovani group and formed a novel haplotype. This was the first report on molecular detection of L. donovani in naturally infected P. chinensi from China.
	PMID: 21254870 [PubMed - as supplied by publisher]
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