Wednesday, July 1, 2009

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 13

1: Mol Genet Genomics. 2009 Jun 30. [Epub ahead of print]Click here to read

EST sequencing of blood-fed and Leishmania-infected midgut of Lutzomyia longipalpis, the principal visceral leishmaniasis vector in the Americas.

Pitaluga AN, Beteille V, Lobo AR, Ortigão-Farias JR, Dávila AM, Souza AA, Ramalho-Ortigão JM, Traub-Cseko YM.

Laboratório de Biologia Molecular de Tripanosomatídeos e Flebotomíneos, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, RJ, 21045-900, Brazil.

Leishmaniasis is an important worldwide public health problem. Visceral leishmaniasis caused by Leishmania infantum chagasi is mainly transmitted by Lutzomyia longipalpis in the Americas. Leishmania development within the sand fly vector is mostly restricted to the midgut. Thus, a comparative analysis of blood-fed versus infected midguts may provide an invaluable insight into various aspects of sand fly immunity, physiology of blood digestion, and, more importantly, of Leishmania development. To that end, we have engaged in a study to identify expressed sequenced tags (ESTs) from L. longipalpis cDNA libraries produced from midguts dissected at different times post blood meal and also after artificial infection with L. i. chagasi. A total of 2,520 ESTs were obtained and, according to the quality of the sequencing data obtained, assembled into 378 clusters and 1,526 individual sequences or singletons totalizing 1,904 sequences. Several sequences associated with defense, apoptosis, RNAi, and digestion processes were annotated. The data presented here increases current knowledge on the New World sand fly transcriptome, contributing to the understanding of various aspects of the molecular physiology of L. longipalpis, and mechanisms underlying the relationship of this sand fly species with L. i. chagasi.

PMID: 19565270 [PubMed - as supplied by publisher]

2: J Leukoc Biol. 2009 Jun 29. [Epub ahead of print]Click here to read

Protein disulfide isomerase (PDI) associates with NADPH oxidase and is required for phagocytosis of Leishmania chagasi promastigotes by macrophages.

Santos CX, Stolf BS, Takemoto PV, Amanso AM, Lopes LR, Souza EB, Goto H, Laurindo FR.

*Vascular Biology Laboratory, Heart Institute (InCor), andTropical Medicine Institute, School of Medicine, and Departments ofParasitology andPharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

PDI, a redox chaperone, is involved in host cell uptake of bacteria/viruses, phagosome formation, and vascular NADPH oxidase regulation. PDI involvement in phagocyte infection by parasites has been poorly explored. Here, we investigated the role of PDI in in vitro infection of J774 macrophages by amastigote and promastigote forms of the protozoan Leishmania chagasi and assessed whether PDI associates with the macrophage NADPH oxidase complex. Promastigote but not amastigote phagocytosis was inhibited significantly by macrophage incubation with thiol/PDI inhibitors DTNB, bacitracin, phenylarsine oxide, and neutralizing PDI antibody in a parasite redox-dependent way. Binding assays indicate that PDI preferentially mediates parasite internalization. Bref-A, an ER-Golgi-disrupting agent, prevented PDI concentration in an enriched macrophage membrane fraction and promoted a significant decrease in infection. Promastigote phagocytosis was increased further by macrophage overexpression of wild-type PDI and decreased upon transfection with an antisense PDI plasmid or PDI siRNA. At later stages of infection, PDI physically interacted with L. chagasi, as revealed by immunoprecipitation data. Promastigote uptake was inhibited consistently by macrophage preincubation with catalase. Additionally, loss- or gain-of-function experiments indicated that PMA-driven NADPH oxidase activation correlated directly with PDI expression levels. Close association between PDI and the p22phox NADPH oxidase subunit was shown by confocal colocalization and coimmunoprecipitation. These results provide evidence that PDI not only associates with phagocyte NADPH oxidase but also that PDI is crucial for efficient macrophage infection by L. chagasi.

PMID: 19564574 [PubMed - as supplied by publisher]

3: Antimicrob Agents Chemother. 2009 Jun 29. [Epub ahead of print]Click here to read

Antiprotozoal activity of 1-phenethyl-4-aminopiperidine derivatives.

Dardonville C, Fernandez-Fernandez C, Gibbons SL, Jagerovic N, Nieto L, Ryan G, Kaiser M, Brun R.

Instituto de Química Médica, CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain; Swiss Tropical Institute, Socinstrasse, 57, CH-4002 Basel, Switzerland.

A series of forty four 4-aminopiperidine derivatives was screened in vitro against four protozoan parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum). This screening identified 29 molecules selectively active against bloodstream form T. b. rhodesiense trypomastigotes with IC50 values ranging from 0.12 to 10 microM, and 33 compounds active against the chloroquine/pyrimethamine resistant K1 strain of P. falciparum in the range 0.17 to 5 microM. In addition, seven compounds displayed activity against intracellular T. cruzi amastigotes, in the same range as the reference drug benznidazole (IC50 = 1.97 microM), but were also cytotoxic to L6-cells showing little selectivity for T. cruzi. None of the molecules tested showed interesting antileishmanial activity against axenic amastigotes of L. donovani. To our knowledge, this is the first report of the antitrypanosomal activity of molecules bearing the 4-aminopiperidine skeleton.

PMID: 19564359 [PubMed - as supplied by publisher]

4: Am J Otolaryngol. 2009 Jul-Aug;30(4):285-7. Epub 2009 Feb 6.Click here to read

Leishmaniasis of the auricle mimicking carcinoma.

Sabri A, Khatib L, Kanj-Sharara S, Husseini ST, Nuwayri-Salti N, Semaan R, Rameh C.

Department of Otolaryngology-Head and Neck Surgery, American University of Beirut Medical Center, Beirut, Lebanon. as71@aub.edu.lb

Leishmaniasis of the auricle has been rarely reported in our region of the world, where it is labeled as "Old World Leishmaniasis." It may mimic other pathologies, such as malignancies or other infectious processes. We present a case of an auricular Leishmania lesion which was first suspected to be a carcinoma. Four previous auricular Old World Leishmania cases have been reported. The epidemiology, clinical presentation, diagnosis, and treatment of this entity are briefly reviewed.

PMID: 19563944 [PubMed - in process]

5: Biochim Biophys Acta. 2009 Jun 26. [Epub ahead of print]Click here to read

Leishmania donovani trypanothione reductase: Role of urea and guanidine hydrochloride in modulation of functional and structural properties.

Rai S, Dwivedi UN, Goyal N.

Division of Biochemistry, Central Drug Research Institute, Lucknow-226001, India.

Trypanothione reductase [TR], an NADPH-dependent disulfide oxidoreductase, unique to kinetoplastid parasites including Trypanosoma and Leishmania, is a validated target for the design of improved drugs. TR is a stable homodimer with a FAD molecule tightly bound to each subunit. In this paper, structure, function, stability properties and cofactor protein interactions of recombinant TR from Leishmania donovani were investigated under equilibrium unfolding/denaturing conditions. Urea induced unfolding was non-reductive in nature and led to the formation of partially folded intermediate. This intermediate species lacks catalytic activity and characteristic conformation of native LdTR but has significant secondary structure and could be partially reactivated. Guanidine hydrochloride-induced irreversible denaturation was marked by the presence of molten globule intermediate. Reactivation and cross-linking experiments clearly demonstrated that the loss of activity at lower denaturant concentrations was not coincided by dimer dissociation or structural unfolding. The studies demonstrate that functional conformation and stability is largely governed by ionic interactions and active centre site disulphide plays a vital role in helping to maintaining functional conformation. The results obtained from this study provide intriguing insight into the possible mechanism/s of modulation of structure, function and stability of LdTR induced by the cationic, guanidine hydrochloride and the neutral denaturant, urea.

PMID: 19563920 [PubMed - as supplied by publisher]

6: Int J Health Geogr. 2009 Jun 29;8(1):39. [Epub ahead of print]Click here to read

Optimum land cover products for use in a Glossina-morsitans habitat model of Kenya.

Devisser MH, Messina JP.

ABSTRACT: BACKGROUND: Tsetse flies are the primary vector for African trypanosomiasis, a disease that affects both humans and livestock across the continent of Africa. In 1973 tsetse flies were estimated to inhabit 22% of Kenya; by 1996 that number had risen to roughly 34%. Efforts to control the disease were hampered by a lack of information and costs associated with the identification of infested areas. Given changing spatial and demographic factors, a model that can predict suitable tsetse fly habitat based on land cover and climate change is critical to efforts aimed at controlling the disease. In this paper we present a generalizable method, using a modified Mapcurves goodness of fit test, to evaluate the existing publicly available land cover products to determine which products perform the best at identifying suitable tsetse fly land cover. RESULTS: For single date applications, Africover was determined to be the best land use land cover (LULC) product for tsetse modeling. However, for changing habitats, whether climatically or anthropogenically forced, the IGBP DISCover and MODIS type 1 products where determined to be most practical. CONCLUSION: The method can be used to differentiate between various LULC products and be applied to any such research when there is a known relationship between a species and land cover.

PMID: 19563674 [PubMed - as supplied by publisher]

7: Trop Med Int Health. 2009 Jun 28. [Epub ahead of print]Click here to read

Cost-effectiveness projections of single and combination therapies for visceral leishmaniasis in Bihar, India.

Olliaro P, Darley S, Laxminarayan R, Sundar S.

UNICEF/UNDP/WB/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland.

Summary Objectives To assess the cost-effectiveness of current monotherapies and prospective combinations for treating visceral leishmaniasis (VL) in Bihar, India in terms of years of life lost (YLL) averted as well as deaths averted. Methods We employed two methods to estimate the number of avertable deaths in our analysis: one using estimated mortality, the other using direct incidence estimates for VL. Costs of care are based on an average private hospital in Bihar, and data on drug costs were obtained both locally and from the World Health Organization. Results The cost of monotherapies per averted YLL ranged from US$2 for paromomycin in an outpatient setting to US$20-22 for AmBisome((R)) at 20 mg/kg. The corresponding costs per death averted ranged from US$53-54 to US$523-527. Combinations ranged US$5-8 per YLL averted and US$124-213 per death averted. Conclusion The available treatments for VL are cost-effective, and our mortality and incidence-based methods produce consistent estimates. The combinations considered here were more cost-effective than most monotherapies. Having multiple treatment options and combining drugs are also likely to reduce drug pressure and prolong the drugs' life-span of effective use.

PMID: 19563434 [PubMed - as supplied by publisher]

8: Nat Rev Microbiol. 2009 Jul;7(7):504-13.Click here to read LinkOut

Epigenetic regulation in African trypanosomes: a new kid on the block.

Figueiredo LM, Cross GA, Janzen CJ.

Laboratory of Molecular Parasitology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA. luisa.figueiredo@rockefeller.edu

Epigenetic regulation is important in many facets of eukaryotic biology. Recent work has suggested that the basic mechanisms underlying epigenetic regulation extend to eukaryotic parasites. The identification of post-translational histone modifications and chromatin-modifying enzymes is beginning to reveal both common and novel functions for chromatin in these parasites. In this Review, we compare the role of epigenetics in African trypanosomes and humans in several biological processes. We discuss how the study of trypanosome chromatin might help us to better understand the evolution of epigenetic processes.

PMID: 19528957 [PubMed - indexed for MEDLINE]

9: Nature. 2009 May 14;459(7244):213-7.Click here to read LinkOut
Comment in:
Nature. 2009 May 14;459(7244):175.

A surface transporter family conveys the trypanosome differentiation signal.

Dean S, Marchetti R, Kirk K, Matthews KR.

Centre for Immunity, Infection and Evolution, Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK.

Microbial pathogens use environmental cues to trigger the developmental events needed to infect mammalian hosts or transmit to disease vectors. The parasites causing African sleeping sickness respond to citrate or cis-aconitate (CCA) to initiate life-cycle development when transmitted to their tsetse fly vector. This requires hypersensitization of the parasites to CCA by exposure to low temperature, conditions encountered after tsetse fly feeding at dusk or dawn. Here we identify a carboxylate-transporter family, PAD (proteins associated with differentiation), required for perception of this differentiation signal. Consistent with predictions for the response of trypanosomes to CCA, PAD proteins are expressed on the surface of the transmission-competent 'stumpy-form' parasites in the bloodstream, and at least one member is thermoregulated, showing elevated expression and surface access at low temperature. Moreover, RNA-interference-mediated ablation of PAD expression diminishes CCA-induced differentiation and eliminates CCA hypersensitivity under cold-shock conditions. As well as being molecular transducers of the differentiation signal in these parasites, PAD proteins provide the first example of a surface marker able to discriminate the transmission stage of trypanosomes in their mammalian host.

PMID: 19444208 [PubMed - indexed for MEDLINE]

PMCID: PMC2685892 [Available on 2009/11/14]

10: Nature. 2009 May 14;459(7244):175.Click here to read LinkOut
Comment on:
Nature. 2009 May 14;459(7244):213-7.

Microbiology: Signals for change.

Shadan S.

PMID: 19444199 [PubMed - indexed for MEDLINE]

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