What's new for 'Trypanosomatids' in PubMed

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Sent on Thursday, 2010 Feb 18
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 16

1.	Mar Drugs. 2010 Jan 15;8(1):47-58. Inhibitory Activity of Marine Sponge-Derived Natural Products against Parasitic Protozoa. Orhan I, Sener B, Kaiser M, Brun R, Tasdemir D. Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, TR-06330 Ankara, Turkey; E-Mails: iorhan@gazi.edu.tr (I.O.); bilgesen@gazi.edu.tr (B. S.). In this study, thirteen sponge-derived terpenoids, including five linear furanoterpenes: furospinulosin-1 (1), furospinulosin-2 (2), furospongin-1 (3), furospongin-4 (4), and demethylfurospongin-4 (5); four linear meroterpenes: 2-(hexaprenylmethyl)-2-methylchromenol (6), 4-hydroxy-3-octaprenylbenzoic acid (7), 4-hydroxy-3-tetraprenyl-phenylacetic acid (8), and heptaprenyl-p-quinol (9); a linear triterpene, squalene (10); two spongian-type diterpenes dorisenone D (11) and 11beta-acetoxyspongi-12-en-16-one (12); a scalarane-type sesterterpene; 12-epi-deoxoscalarin (13), as well as an indole alkaloid, tryptophol (14) were screened for their in vitro activity against four parasitic protozoa; Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani and Plasmodium falciparum. Cytotoxic potential of the compounds on mammalian cells was also assessed. All compounds were active against T. brucei rhodesiense, with compound 8 being the most potent (IC(50) 0.60 mug/mL), whereas 9 and 12 were the most active compounds against T. cruzi, with IC(50) values around 4 mug/mL. Compound 12 showed the strongest leishmanicidal activity (IC(50) 0.75 mug/mL), which was comparable to that of miltefosine (IC(50) 0.20 mug/mL). The best antiplasmodial effect was exerted by compound 11 (IC(50) 0.43 mug/mL), followed by compounds 7, 10, and 12 with IC(50) values around 1 mug/mL. Compounds 9, 11 and 12 exhibited, besides their antiprotozoal activity, also some cytotoxicity, whereas all other compounds had low or no cytotoxicity towards the mammalian cell line. This is the first report of antiprotozoal activity of marine metabolites 1-14, and points out the potential of marine sponges in discovery of new antiprotozoal lead compounds.
	PMID: 20161970 [PubMed - in process]

2.	PLoS Negl Trop Dis. 2010 Feb 9;4(2):e599. Of cattle, sand flies and men: a systematic review of risk factor analyses for South asian visceral leishmaniasis and implications for elimination. Bern C, Courtenay O, Alvar J. Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America. BACKGROUND: Studies performed over the past decade have identified fairly consistent epidemiological patterns of risk factors for visceral leishmaniasis (VL) in the Indian subcontinent. METHODS AND PRINCIPAL FINDINGS: To inform the current regional VL elimination effort and identify key gaps in knowledge, we performed a systematic review of the literature, with a special emphasis on data regarding the role of cattle because primary risk factor studies have yielded apparently contradictory results. Because humans form the sole infection reservoir, clustering of kala-azar cases is a prominent epidemiological feature, both at the household level and on a larger scale. Subclinical infection also tends to show clustering around kala-azar cases. Within villages, areas become saturated over a period of several years; kala-azar incidence then decreases while neighboring areas see increases. More recently, post kala-azar dermal leishmaniasis (PKDL) cases have followed kala-azar peaks. Mud walls, palpable dampness in houses, and peri-domestic vegetation may increase infection risk through enhanced density and prolonged survival of the sand fly vector. Bed net use, sleeping on a cot and indoor residual spraying are generally associated with decreased risk. Poor micronutrient status increases the risk of progression to kala-azar. The presence of cattle is associated with increased risk in some studies and decreased risk in others, reflecting the complexity of the effect of bovines on sand fly abundance, aggregation, feeding behavior and leishmanial infection rates. Poverty is an overarching theme, interacting with individual risk factors on multiple levels. CONCLUSIONS: Carefully designed demonstration projects, taking into account the complex web of interconnected risk factors, are needed to provide direct proof of principle for elimination and to identify the most effective maintenance activities to prevent a rapid resurgence when interventions are scaled back. More effective, short-course treatment regimens for PKDL are urgently needed to enable the elimination initiative to succeed.
	PMID: 20161727 [PubMed - in process]

3.	Antimicrob Agents Chemother. 2010 Feb 16. [Epub ahead of print] Inhibitors of Leishmania GDP-Mannose Pyrophosphorylase Identified by High-Throughput Screening of Small Molecule Chemical Library. Lackovic K, Parisot JP, Sleebs N, Baell JB, Debien L, Watson KG, Curtis JM, Handman E, Street IP, Kedzierski L. High-Throughput Chemical Screening Facility, Structural Biology Division, Medicinal Chemistry Group, Structural Biology Division, Infection and Immunity Division, CRC for Cancer Therapeutics, Cancer and Haematology Division, Walter+Eliza Hall Institute of Medical Research, Melbourne, Australia. Current treatment of leishmaniasis is based on chemotherapy, which relies on a handful of drugs with serious limitations such as high cost, toxicity and lack of efficacy in endemic regions. Therefore, development of new, effective and affordable antileishmanial drugs is a global health priority. Leishmania synthesize a range of mannose-rich glycoconjugates that are essential for parasite virulence and survival. A prerequisite for glycoconjugate biosynthesis is the conversion of monosaccharides to activated mannose donor, GDP-mannose, the product of a reaction catalysed by GDP-mannose pyrophosphorylase (GDP-MP). The deletion of the gene encoding GDP-MP in Leishmania led to a total loss of virulence, indicating that the enzyme is an ideal drug target. We developed a phosphate sensor-based high-throughput screening assay to quantify GDP-MP activity, and screened a library containing approximately 80,000 lead-like compounds for GDP-MP inhibitors. Based on their GDP-MP inhibitory properties and chemical structure, 20 compounds, which were not toxic to mammalian cells, were tested on ex vivo amastigotes and in macrophage amastigote assays. The most potent compound identified in the primary screen (compound 3), a quinoline derivative, demonstrated dose-dependent activity in both assays (IC50=21.9muM in macrophage assay) and was shown to be non-toxic to human fibroblasts. In order to elucidate signs of early SAR for this class of compounds, we obtained and tested analogues of compound 3, and undertook limited medicinal chemistry optimization, which included a number of SAR probes of the piperazinyl aryl substituent of compound 3. We have identified novel candidate compounds for the design and synthesis of anti-leishmanial therapeutics.
	PMID: 20160053 [PubMed - as supplied by publisher]

4.	Infect Immun. 2010 Feb 16. [Epub ahead of print] Up-regulated expression of a B-cell antigen family tandem repeat proteins by Leishmania amastigotes. Goto Y, Carter D, Guderian J, Inoue N, Kawazu SI, Reed SG. National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan; Infectious Disease Research Institute, 1124 Columbia Street, Suite 400, Seattle, WA 98104, USA, and; Protein Advances Inc., 1102 Columbia Street, Suite 107, Seattle, WA 98104, USA. Proteins with tandem repeat (TR) domains have been found in various protozoan parasites, often acting as targets of B-cell responses. Through systematic analyses of whole proteomes, we recently demonstrated that two trypanosomatid parasites, Leishmania infantum and Trypanosoma cruzi, are rich in large TR domain-containing proteins with immunological significance. However, the reason why these proteins are antigenic remained unclear. Here, through molecular, immunological and bioinformatic characterizations of Leishmania TR proteins, we found two possible factors affecting their antigenicity: one is derived from their fundamental character as TR proteins, and the other is through regulation of their expression by parasites. ELISAs using recombinant proteins revealed that the copy number of the repeat affects the binding affinity between antigens and antibodies as expected by thermodynamic binding kinetics. Other than containing TR domains, these proteins do not share such characteristics as sequence similarity or biased cellular location predicted by the presence of signal sequence(s) and/or trans-membrane domain(s). However, the TR proteome contained a higher ratio of proteins up-regulated in amastigotes than the whole proteome, and such an up-regulated expression of a TR protein seemed to affect its antigenicity. These results indicate that Leishmania parasites actively utilize the TR protein family for parasitism in mammalian hosts.
	PMID: 20160013 [PubMed - as supplied by publisher]

5.	Nucleic Acids Res. 2010 Feb 16. [Epub ahead of print] Establishment of an in vitro trans-splicing system in Trypanosoma brucei that requires endogenous spliced leader RNA. Shaked H, Wachtel C, Tulinski P, Yahia NH, Barda O, Darzynkiewicz E, Nilsen TW, Michaeli S. The Mina & Everard Goodman Faculty of Life Sciences, and Advanced Materials and Nanotechnology Institute Bar-Ilan University, Ramat-Gan 52900, Israel, Department of Biophysics, Institute of Experimental Physics, Warsaw University, 02-089, Warsaw, Poland and Center for RNA Molecular Biology, Case Western Reserve University, School of Medicine, W127, 10900 Euclid Avenue Cleveland, OH 44106-4973, USA. In trypanosomes a 39 nucleotide exon, the spliced leader (SL) is donated to all mRNAs from a small RNA, the SL RNA, by trans-splicing. Since the discovery of trans-splicing in trypanosomes two decades ago, numerous attempts failed to reconstitute the reaction in vitro. In this study, a crude whole-cell extract utilizing the endogenous SL RNA and synthetic tubulin pre-mRNA were used to reconstitute the trans-splicing reaction. An RNase protection assay was used to detect the trans-spliced product. The reaction was optimized and shown to depend on ATP and intact U2 and U6 snRNPs. Mutations introduced at the polypyrimidine tract and the AG splice site reduced the reaction efficiency. To simplify the assay, RT-PCR and quantitative real-time PCR assays were established. The system was used to examine the structural requirements for SL RNA as a substrate in the reaction. Interestingly, synthetic SL RNA assembled poorly to its cognate particle and was not utilized in the reaction. However, SL RNA synthesized in cells lacking Sm proteins, which is defective in cap-4 modification, was active in the reaction. This study is the first step towards further elucidating the mechanism of trans-splicing, an essential reaction which determines the trypanosome transcriptome.
	PMID: 20159996 [PubMed - as supplied by publisher]

6.	J Cell Sci. 2010 Feb 16. [Epub ahead of print] An exosome-based secretion pathway is responsible for protein export from Leishmania and communication with macrophages. Silverman JM, Clos J, De'oliveira CC, Shirvani O, Fang Y, Wang C, Foster LJ, Reiner NE. Specialized secretion systems are used by numerous bacterial pathogens to export virulence factors into host target cells. Leishmania and other eukaryotic intracellular pathogens also deliver effector proteins into host cells; however, the mechanisms involved have remained elusive. In this report, we identify exosome-based secretion as a general mechanism for protein secretion by Leishmania, and show that exosomes are involved in the delivery of proteins into host target cells. Comparative quantitative proteomics unambiguously identified 329 proteins in Leishmania exosomes, accounting for >52% of global protein secretion from these organisms. Our findings demonstrate that infection-like stressors (37 degrees C +/- pH 5.5 upregulated exosome release more than twofold and also modified exosome protein composition. Leishmania exosomes and exosomal proteins were detected in the cytosolic compartment of infected macrophages and incubation of macrophages with exosomes selectively induced secretion of IL-8, but not TNF-alpha. We thus provide evidence for an apparently broad-based mechanism of protein export by Leishmania. Moreover, we describe a mechanism for the direct delivery of Leishmania molecules into macrophages. These findings suggest that, like mammalian exosomes, Leishmania exosomes function in long-range communication and immune modulation.
	PMID: 20159964 [PubMed - as supplied by publisher]

7.	J Am Acad Dermatol. 2010 Mar;62(3):508-10. Cutaneous leishmaniasis in Texas. McHugh CP. Epidemiology Consult Service, US Air Force School of Aerospace Medicine, Brooks City-Base, Texas.
	PMID: 20159317 [PubMed - in process]
	Publication Types: Letter

8.	Exp Parasitol. 2010 Feb 13. [Epub ahead of print] Interactions of antimicrobial peptides with Leishmania and trypanosomes and their functional role in host parasitism. McGwire BS, Kulkarni MM. Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio; Division of Infectious Diseases, Department of Internal Medicine, The Ohio State University, Columbus, Ohio. Antimicrobial peptides (AMPs) are multifunctional components of the innate systems of both insect and mammalian hosts of the pathogenic trypanosomatids Leishmania and Trypanosoma species. Structurally diverse AMPs from a wide range of organisms have been shown to have in vitro activity against these parasites acting mainly to disrupt surface-membranes. In some cases AMPs also localize intracellularly to affect calcium levels, mitochondrial function and the induction of autophagy, necrosis and apoptosis. In this review we discuss the work done in the area of AMP interactions with trypanosomatid protozoa and propose potential targets of AMP activity at the cellular level as well as how AMPs might influence parasite growth and differentiation in their hosts to determine the outcome of natural infection. Copyright © 2010. Published by Elsevier Inc.
	PMID: 20159013 [PubMed - as supplied by publisher]

9.	Parasitology. 2010 Feb 17:1-11. [Epub ahead of print] Central carbon metabolism of Leishmania parasites.< /h1>Saunders EC, DE Souza DP, Naderer T, Sernee MF, Ralton JE, Doyle MA, Macrae JI, Chambers JL, Heng J, Nahid A, Likic VA, McConville MJ. Department of Biochemistry and Molecular Biology, University of Melbourne, 30 Flemington Rd, Parkville, 3010, Victoria, Australia. SUMMARYLeishmania spp. are sandfly-transmitted protozoa parasites that cause a spectrum of diseases in humans. Many enzymes involved in Leishmania central carbon metabolism differ from their equivalents in the mammalian host and are potential drug targets. In this review we summarize recent advances in our understanding of Leishmania central carbon metabolism, focusing on pathways of carbon utilization that are required for growth and pathogenesis in the mammalian host. While Leishmania central carbon metabolism shares many features in common with other pathogenic trypanosomatids, significant differences are also apparent. Leishmania parasites are also unusual in constitutively expressing most core metabolic pathways throughout their life cycle, a feature that may allow these parasites to exploit a range of different carbon sources (primarily sugars and amino acids) rapidly in both the insect vector and vertebrate host. Indeed, recent gene deletion studies suggest that mammal-infective stages are dependent on multiple carbon sources in vivo. The application of metabolomic approaches, outlined here, are likely to be important in defining aspects of central carbon metabolism that are essential at different stages of mammalian host infection.
	PMID: 20158936 [PubMed - as supplied by publisher]

10.	Endocr Metab Immune Disord Drug Targets. 2010 Feb 17. [Epub ahead of print] The Central role of Macrophages in Trypanosomiasis-Associated Anemia: Rationale for Therapeutical Approaches. Stijlemans B, Vankrunkelsven A, Caljon G, Bockstal V, Guilliams M, Bosschaerts T, Beschin A, Raes G, Magez S, De Baetselier P. VIB Department of Molecular and Cellular Interactions, Vrije Universiteit Brussel (VUB), Laboratory of Cellular and Molecular Immunology, Building E, Level 8, Pleinlaan 2, B-1050 Brussels, Belgium. bstijlem@vub.ac.be. Bovine African trypanosomiasis causes severe economical problems on the African continent and one of the most prominent immunopathological parameters associated with this parasitic infection is anemia. In this report we review the current knowledge of the mechanisms underlying trypanosomiasis-associated anemia. In first instance, the central role of macrophages and particularly their activation state in determining the outcome of the disease (i.e. trypanosusceptibility versus trypanotolerance) will be discussed. In essence, while persistence of classically activated macrophages (M1) contributes to anemia development, switching towards alternatively activated macrophages (M2) alleviates pathology including anemia. Secondly, while parasite-derived glycolipids such as the glycosylphosphatidylinositol (GPI) induce M1, host-derived IL-10 blocks M1-mediated inflammation, promotes M2 development and prevents anemia development. In this context, strategies aimed at inducing the M1 to M2 switch, such as GPI-based treatment, adenoviral delivery of IL-10 and induction of IL-10 producing regulatory T cells will be discussed. Finally, the crucial role of iron-homeostasis in trypanosomiasis-associated anemia development will be documented to stress the analogy with anemia of chronic disease (ACD), hereby providing new insight that might contribute to the treatment of ACD.
	PMID: 20158497 [PubMed - as supplied by publisher]