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Sent on Wednesday, 2010 Apr 07Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | Antimicrob Agents Chemother. 2010 Apr 5. [Epub ahead of print]Novel Arylimidamides for the Treatment of Visceral Leishmaniasis.Wang MZ, Zhu X, Srivastava A, Liu Q, Sweat JM, Pandharkar T, Stephens CE, Riccio E, Parman T, Munde M, Mandal S, Madhubala R, Tidwell RR, Wilson WD, Boykin DW, Hall JE, Kyle DE, Werbovetz KA.Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; Department of Global Health, College of Public Health, University of South Florida, Tampa, FL 33612, USA; Department of Pathology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Chemistry and Physics, Augusta State University, Augusta, GA 30904, USA; SRI International, Menlo Park, California, USA; Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA; School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India. AbstractArylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (IC50 < 1 muM) against both Leishmania donovani axenic amastigotes and intracellular Leishmania, the causative agent for human visceral leishmaniasis (VL). A systematic lead discovery program was employed to characterize in vitro and in vivo antileishmanial activities, pharmacokinetics, mutagenicity, and toxicity of two novel AIAs, DB745 and DB766. They were exceptionally active (IC50 </= 0.12 muM) against intracellular L. donovani, L. amazonensis and L. major, and did not exhibit mutagenicity in an Ames screen. DB745 and DB766, given orally, produced a dose-dependent inhibition of liver parasitemia in two efficacy models, L. donovani-infected mice and hamsters. Most notably, DB766 (100 mg/kg/day for 5 days) reduced liver parasitemia in mice and hamsters by 71% and 89%, respectively. Marked reduction of parasitemia in the spleen (79%) and bone marrow (92%) of hamsters was also observed. Furthermore, these compounds distributed to target tissues (liver and spleen); had a moderate oral bioavailability (up to 25%), a large volume of distribution, and an elimination half-life ranging from one to two days in mice. In a repeat-dose toxicity study in mice, there was no indication of liver or kidney toxicity for DB766 from serum chemistries, although mild hepatic cell eosinophilia, hypertrophy, and fatty changes were noted. These results demonstrated that arylimidamides are a promising class of molecules that possesses good antileishmanial activity and desirable pharmacokinetics, and should be considered for further preclinical development as an oral treatment for VL. |
| PMID: 20368397 [PubMed - as supplied by publisher] | |
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| 2. | Infect Immun. 2010 Apr 5. [Epub ahead of print]Comparative Study of the Ability of Leishmania mexicana Promastigotes and Amastigotes to Alter Macrophage Signalling and Functio ns.Abu-Dayyeh I, Hassani K, Westra ER, Mottram JC, Olivier M.Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada; Centre for the Study of Host Resistance, The Research Institute of the McGill University Health Centre, Montréal, QC, H3A 2B4, Canada; Laboratory of Microbiology, Department of Agrotechnology and Food Sciences, Wageningen University, Dreijenplein 10, 6703 HB Wageningen, Netherlands; Wellcome Centre for Molecular Parasitology and Division of Infection & Immunity, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK. AbstractLeishmania alternates between two morphologically different stages: promastigotes and amastigotes. While the majority of reports focused on how the promastigote form can alter macrophage (MØ) signalling and function, fewer reports investigated signalling alterations mediated by amastigotes, and comparative studies are lacking. In this study, we performed a comparison between the ability of both forms of the parasite to alter MØ signalling and functions. Here, we show that promastigotes and amastigotes were both able to rapidly activate host protein tyrosine phosphatases (PTPs), importantly the Src-homology 2 domain-containing PTP (SHP-1). However, we found that PTP-1B is specifically activated by promastigote but not amastigote infection and that lmcpb(-/-) promastigotes were no longer able to activate PTP-1B. We also show a similarity in the way promastigotes and amastigotes inactivate the transcription factors (TFs) STAT-1alpha and AP-1, but differences in the modulation of NF-kappaB with promastigotes cleaving the p65 subunit generating a smaller p35 subunit while amastigotes fully degrading the p65 subunit with no p35 production. Importantly, we show that the cysteine proteinase LmCPb plays a key role in the alteration of NF-kappaB, STAT-1alpha, and AP-1 by promastigote and amastigote infections, ultimately leading to the inability of these TFs to translocate to the nucleus in response to IFN-gamma stimulation and thus contributing to the ability of both parasite forms to effectively block IFN-gamma-mediated NO production in MØs. |
| PMID: 20368344 [PubMed - as supplied by publisher] | |
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| 3. | Infect Immun. 2010 Apr 5. [Epub ahead of print]Fine mapping of Leishmania major susceptibility locus lmr2: evidence for a role for Fli1 in disease and wound healing.Sakthianandeswaren A, Curtis JM, Elso C, Kumar B, Baldwin TM, Lopaticki S, Kedzierski L, Smyth GK, Foote SJ, Handman E.Infection and Immunity Division, The Walter and Eliza Hall Institute, 1G Royal Parade, Parkville 3050, Victoria, Australia; Department of Medical Biology, University of Melbourne, Parkville 3050, Victoria, Australia; Menzies Research Institute, 17, Liverpool St, Hobart 7000, Tasmania, Australia. AbstractGenetic linkage studies on the host response to Leishmania major, the causative agent of cutaneous leishmaniasis, have identified significant genetic complexity in humans and mice. In the mouse model, multiple loci have been implicated in susceptibility to infection but to date the genes underlying these loci have not been identified. We now describe the contribution of a novel candidate gene, Fli1, to both L. major resistance and enhanced wound healing. We have previously mapped the L. major response locus, lmr2, to proximal chromosome 9, in a genetic cross between the resistant C57BL/6 and susceptible BALB/c mice. We now show that the presence of the resistant C57BL/6 lmr2 allele in susceptible BALB/c mice confers an enhanced L. major resistance and wound healing phenotype. Fine-mapping of the lmr2 locus permitted the localisation of the lmr2 QTL to a 5Mb interval comprising 21 genes, of which microarray analysis was able to identify differential expression of 1 gene- Fli1. Analysis of Fli1 expression in wounded and L. major infected skin and lymph node validated the importance of Fli1 in lesion resolution and wound healing, and identified 3 polymorphisms in the Fli1 promoter of which a GA repeat element may be the important contributor. |
| PMID: 20368343 [PubMed - as supplied by publisher] | |
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| 4. | Med J Aust. 2010 Apr 5;192(7):417-9.Late-stage human African trypanosomiasis in a Sudanese refugee.Cherian P, Junckerstorff RK, Rosen D, Kumarasinghe P, Morling A, Tuch P, Raven S, Murray RJ, Heath CH.Royal Perth Hospital, Perth, WA, Australia. pcherian1@hotmail.com. AbstractA 19-year-old Sudanese woman, who had lived for about a decade in Ugandan refugee camps, was referred for investigation of a 12-month history of a generalised rash. Two months later, her condition had deteriorated to include cachexia and drowsiness. Despite initial negative findings on investigation, human African trypanosomiasis (HAT) was suspected, and parasites were found in a double-centrifuged sample of cerebrospinal fluid. Eflornithine, the appropriate drug for treatment of late-stage disease, was obtained through the World Health Organization. This case highlights the diagnostic and therapeutic difficulties in managing late-stage HAT in a non-endemic country. |
| PMID: 20367593 [PubMed - in process] | |
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| 5. | J Biol Chem. 2010 Apr 2. [Epub ahead of print]Amplification of adenine phosphoribosyltransferase suppresses t he conditionally lethal growth and virulence phenotype of Leishmania donovani mutants lacking both hypoxanthine-guanine and xanthine phosphoribosyltransferase.Boitz JM, Ullman B.Oregon Health & Sciences University; AbstractLeishmania donovani cannot synthesize purines de novo and obligatorily scavenge purines from the host. Previously, we described a conditional lethal hgprt/xprt mutant of L. donovani (Boitz, J. M. and Ullman, B. (2006) J Biol Chem 281, 16084-16089) that establishes that L. donovani salvages purines primarily through hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and xanthine phosphoribosyltransferase (XPRT). Unlike wild type L. donovani, the hgprt/xprt knockout cannot grow on 6-oxypurines and displays an absolute requirement for adenine or adenosine and 2'-deoxycoformycin, an inhibitor of parasite adenine aminohydrolase activity. Here, we demonstrate that the ability of hgprt/xprt parasites to infect mice was profoundly compromised. Surprisingly, mutant parasites that survived the initial passage through mice partially regained their virulence properties, exhibiting a >10-fold increase in parasite burden in a subsequent mouse infection. To dissect the mechanism by which Deltahgprt/Deltaxprt parasites persisted in vivo, suppressor strains that had regained their capacity to grow under restrictive conditions were cloned from cultured Deltahgprt/Deltaxprt parasites. The ability of these suppressor clones to grow in and metabolize 6-oxypurines could be ascribed to a marked amplification and overexpression of the adenine phosphoribosyltransferase (APRT) gene. Moreover, transfection of hgprt/xprt cells with an APRT episome recapitulated the suppressor phenotype in vitro and enabled growth on 6-oxypurines. Biochemical studies further showed that hypoxanthine, unexpectedly, was an inefficient substrate for APRT, evidence that could account for the ability of the suppressors to metabolize hypoxanthine. Subsequent analysis implied that APRT amplification was also a potential contributory mechanism by which Deltahgprt/Deltaxprt parasites displayed persistence and increased virulence in mice. |
| PMID: 20363738 [PubMed - as supplied by publisher] | |
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| 6. | Mol Biochem Parasitol. 2010 Apr 1. [Epub ahead of print]Processing of a phosphoglycerate kinase reporter mRNA in Trypanosoma brucei is not coupled to transcription by RNA polymerase II.Stewart M, Haile S, Jha BA, Cristodero M, Li CH, Clayton C.Zentrum für Molekularbiologie der Universität Heidelberg, ZMBH-DKFZ Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany. AbstractCapping of mRNAs is strictly coupled to RNA polymerase II transcription and there is evidence, mainly from metazoans, that other steps in pre-mRNA processing show a similar linkage. In trypanosomes, however, the mRNA cap is supplied by a trans spliced leader sequence. Thus pre-mRNAs transcribed by RNA Polymerase I are capped by trans splicing, and translation-competent transgenic mRNAs can be produced by RNA Polymerase I and T7 RNA Polymerase so long as the primary transcript has a splice acceptor signal. We quantified the efficiency of processing of trypanosome pre-mRNAs produced from a plasmid integrated either at the tubulin locus, or in an rRNA spacer, and transcribed by RNA polymerase II, RNA polymerase I or T7 RNA polymerase. The processing efficiencies were similar for primary transcripts from the tubulin locus, produced by RNA polymerase II, and for RNA from an rRNA spacer, transcribed by RNA polymerase I. Primary transcripts produced by T7 RNA polymerase from the tubulin locus were processed almost as well. There was therefore no evidence for recruitment of the 3'-splicing apparatus by the RNA polymerase. Abundant transcripts transcribed from the rRNA locus by T7 RNA polymerase were somewhat less efficiently processed. Copyright © 2010. Published by Elsevier B.V. |
| PMID: 20363263 [PubMed - as supplied by publisher] | |
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| 7. | J Mol Biol. 2010 Mar 31. [Epub ahead of print]Mechanism of U-insertion RNA Editing in Trypanosome Mitochondria: The Bimodal TUTase Activity of the Core Complex.Ringpis GE, Aphasizheva I, Wang X, Huang L, Lathrop RH, Hatfield GW, Aphasizhev R.Department of Microbiology & Molecular Genetics, University of California Irvine, California, 92697, USA. AbstractExpression of the trypanosomal mitochondrial genome requires the insertion and deletion of uridylyl residues at specific sites in pre-mRNAs. RET2 terminal uridylyl transferase (TUTase) is an integral component of the RNA editing core complex (RECC) and is responsible for the guide RNA-dependent U-insertion reaction. By analyzing RNAi-based knock-in Trypanosoma brucei cell lines, purified editing complex and individual protein, we have investigated RET2's association with the RECC. In addition, the U-insertion activity exhibited by RET2 as RECC subunit was compared with characteristics of the monomeric protein. We show that RET2 interaction with RECC is accomplished via a protein-protein contact between its middle domain and a structural subunit MP81. The recombinant RET2 catalyzes a faithful editing on gapped (pre-cleaved) double-stranded RNA substrates and this reaction requires an internal monophosphate group at the 5'-end of the mRNA 3'-cleavage fragment. However, RET2 processivity is limited to insertion of three Us. Incorporation into the RECC voids the internal phosphate requirement and allows filling of longer gaps similar to those observed in vivo. Remarkably, monomeric and RECC-embedded enzymes display a similar bimodal activity: the distributive insertion of a single uracil is followed with a processive extension limited by the number of guiding nucleotides. Based on the RNA substrate specificity of RET2 and purine-rich nature of U-insertion sites, we propose that the distributive +1 insertion creates a substrate for the processive gap-filling reaction. Upon base-pairing of the +1-extended 5'-cleavage fragment with a guiding nucleotide, this substrate is recognized by RET2 in a different mode as compared to the product of the initial nucleolytic cleavage. Therefore, RET2 distinguishes base-pairs in gapped RNA substrates which may constitute an additional checkpoint contributing to overall fidelity of the editing process. Copyright © 2010. Published by Elsevier Ltd. |
| PMID: 20362585 [PubMed - as supplied by publisher] | |
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| 8. | Cytokine. 2010 Jan;49(1):64-72. Epub 2009 Nov 4.Tumor necros is factor alpha induced by Trypanosoma cruzi infection mediates inflammation and cell death in the liver of infected mice.Ronco MT, Francés DE, Ingaramo PI, Quiroga AD, Alvarez ML, Pisani GB, Revelli SS, Carnovale CE.Instituto de Fisiología Experimental - CONICET, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Argentina. AbstractTrypanosoma cruzi (T. cruzi) infected C57BL/6 mice developed a progressive fatal disease due to an imbalance in the profile of circulating related compounds accompanying infection like tumor necrosis factor alpha (TNFalpha). TNFalpha has been proposed as an important effector molecule in apoptosis. In this work, we evaluate inflammation and the proteins involved in apoptotic process in liver of infected mice and the role of TNFalpha. C57BL6/mice were infected subcutaneously with 100 viable trypomastigotes of Tulahuén strain of T cruzi. One set of these animals were treated with 375 microg of antihuman TNFalpha blocking antibody. Animals were sacrificed at 14 days post-infection (p.i).The analyses of Bcl-2 family proteins revealed an increase of the pro-apoptotic proteins Bax and tBid in T. cruzi-infected mice. Compared with control animals, cytochrome c release was increased. Apoptosis was also induced in infected mice. Anti-TNFalpha treatment decreases hepatic apoptosis. Our results suggest that T. cruzi infection induces programmed cell death in the host liver by increase of TNFalpha production, associated with TNF-R1 over-expression, that set in motion the Bid cleavage and mitochondrial translocation, Bax mitochondrial translocation, cytochrome c release, and ultimately apoptosis induction. Copyright 2009 Elsevier Ltd. All rights reserved. |
| PMID: 19892564 [PubMed - indexed for MEDLINE] | |
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| 9. | Parasitology. 2010 Feb;137(2):261-73. Epub 2009 Oct 23.Blood parasitaemia in a high latitude flexible breeder, the white-winged crossbill, Loxia leucoptera: contribution of seasonal relapse versus new inoculations.Deviche P, Fokidis HB, Lerbour B, Greiner E.School of Life Sciences, Arizona State University, Tempe, AZ 87287-4501, USA. deviche@asu.edu AbstractWe measured seasonal changes in the prevalence of haematozoa (Leucocytozoon fringillinarum, Haemoproteus fringillae, and Trypanosoma avium) in free-ranging White-winged Crossbills, Loxia leucoptera, over 1.5 year in Fairbanks, Alaska, USA. This prevalence was low during early winter. L. fringillinarum prevalence increased in late winter/early spring, in the absence of vectors, suggesting relapse of latent infection. By contrast, the prevalence of T. avium and H. fringillae did not increase until mid-spring, coincident with the emergence of putative vectors and suggestive of new inoculations. The winter breeding period was not associated with lower body condition or elevated blood heterophil/lymphocyte ratios than the summer post-breeding period. Thus, birds unlikely perceived their breeding effort as particularly stressful. Adult males in May and June had low plasma testosterone and their blood prevalence of L. fringillinarum, but not other haemoparasites, was higher than in adult females. This difference may have resulted from sex differences in behaviour and/or plumage colouration - bright red in males, dull green/yellow in females. Species in which reproduction and vector abundance are seasonally dissociated may constitute important models for investigating the respective contribution of reproductive hormones, breeding effort, and vector abundance to patent and latent hemoparasitic infections and to new inoculations. |
| PMID: 19849885 [PubMed - indexed for MEDLINE] | |
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| 10. | Parasitology. 2010 Feb;137(2):251-9. Epub 2009 Sep 21.Biological, ultrastructural effect and subcellular localization of aromatic diamidines in Trypanosoma cruzi.Batista DG, Pacheco MG, Kumar A, Branowska D, Ismail MA, Hu L, Boykin DW, Soeiro MN.Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, 962 RJ, Brazil. AbstractNo vaccines or safe chemotherapy are available for Chagas disease. Pentamidine and related di-cations are DNA minor groove-binders with broad-spectrum anti-protozoal activity. Therefore our aim was to evaluate the in vitro efficacy of di-cationic compounds - DB1645, DB1582, DB1651, DB1646, DB1670 and DB1627 - against bloodstream trypomastigotes (BT) and intracellular forms of Trypanosoma cruzi. Cellular targets of these compounds in treated parasites were also analysed by fluorescence and transmission electron microscopy (TEM). DB1645, DB1582 and DB1651 were the most active against BT showing IC50 values ranging between 0.15 and 6.9 microm. All compounds displayed low toxicity towards mammalian cells and DB1645, DB1582 and DB1651 were also the most effective against intracellular parasites, with IC50 values ranging between 7.3 and 13.3 microm. All compounds localized in parasite nuclei and kDNA (with greater intensity in the latter structure), and DB1582 and DB1651 also concentrated in non-DNA-containing cytoplasmic organelles possibly acidocalcisomes. TEM revealed alterations in mitochondria and kinetoplasts, as well as important disorganization of microtubules. Our data provide further information regarding the activity of this class of compounds upon T. cruzi which should aid future design and synthesis of agents that could be used for Chagas disease therapy. |
| PMID: 19765349 [PubMed - indexed for MEDLINE] | |
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