Tuesday, April 28, 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 14

1: Med Microbiol Immunol. 2009 Apr 25. [Epub ahead of print]Click here to read

What determines the success or failure of intracellular cutaneous parasites? Lessons learned from leishmaniasis.

Maurer M, Dondji B, von Stebut E.

Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Most parasitic skin infections are averted by very efficient strategies of preventing pathogen invasion. Innate immune cells such as mast cells, macrophages and dendritic cells are responsible for detecting parasites and for recruiting proinflammatory cells that help to contain and control the pathogen at sites of infection. This induces efficient adaptive immunity, which is crucially important for parasite control. Using the example of cutaneous leishmaniasis, we highlight how the skin utilizes different strategies to prevent skin infection and how containment of the infection to the skin site may reduce the harm that otherwise may result for the entire organism.

PMID: 19396461 [PubMed - as supplied by publisher]

2: Curr Genet. 2009 Apr 25. [Epub ahead of print]Click here to read

PTR1-dependent synthesis of tetrahydrobiopterin contributes to oxidant susceptibility in the trypanosomatid protozoan parasite Leishmania major.

Nare B, Garraway LA, Vickers TJ, Beverley SM.

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA, 02115, USA.

Leishmania must survive oxidative stress, but lack many classical antioxidant enzymes and rely heavily on trypanothione-dependent pathways. We used forward genetic screens to recover loci mediating oxidant resistance via overexpression in Leishmania major, which identified pteridine reductase 1 (PTR1). Comparisons of isogenic lines showed ptr1 (-) null mutants were 18-fold more sensitive to H(2)O(2) than PTR1-overproducing lines, and significant three- to fivefold differences were seen with a broad panel of oxidant-inducing agents. The toxicities of simple nitric oxide generators and other drug classes (except antifolates) were unaffected by PTR1 levels. H(2)O(2) susceptibility could be modulated by exogenous biopterin but not folate, in a PTR1- but not dihydrofolate reductase-dependent manner, implicating H(4)B metabolism specifically. Neither H(2)O(2) consumption nor the level of intracellular oxidative stress was affected by PTR1 levels. Coupled with the fact that reduced pteridines are at least 100-fold less abundant than cellular thiols, these data argue strongly that reduced pteridines act through a mechanism other than scavenging. The ability of unconjugated pteridines to counter oxidative stress has implications to infectivity and response to chemotherapy. Since the intracellular pteridine levels of Leishmania can be readily manipulated, these organisms offer a powerful setting for the dissection of pteridine-dependent oxidant susceptibility in higher eukaryotes.

PMID: 19396443 [PubMed - as supplied by publisher]

3: Bioorg Med Chem. 2009 Apr 7. [Epub ahead of print]Click here to read

Antiplasmodial and antitrypanosomal activity of bicyclic amides and esters of dialkylamino acids.

Faist J, Seebacher W, Schlapper C, Kaiser M, Brun R, Saf R, Weis R.

Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Universitätsplatz 1, A-8010 Graz, Austria.

Several bicyclic amides and esters of dialkylamino acids were prepared. Their activities against a multiresistant strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900) were examined. Structure-activity relationships were discussed. Particularly the ester compounds showed good antiplasmodial and antitrypanosomal activity and a single compound was tested in vivo against Plasmodium berghei.

PMID: 19395265 [PubMed - as supplied by publisher]

4: Rev Med Interne. 2009 Apr 24. [Epub ahead of print]Click here to read

[Update on visceral Mediterranean leishmaniasis.]

[Article in French]

Rosenthal E, Marty P.

Service de médecine interne, hôpital de l'Archet, centre hospitalier universitaire de Nice, 151, route de Saint-Antoine de Ginestière, 06202 Nice cedex 3, France.

PMID: 19394722 [PubMed - as supplied by publisher]

5: Exp Parasitol. 2009 Apr 21. [Epub ahead of print]Click here to read

Flow cytometric determination of intracellular non-protein thiols in Leishmania promastigotes using 5-chloromethyl fluorescein diacetate.

Sarkar A, Mandal G, Singh N, Sundar S, Chatterjee M.

Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, 244B Acharya JC Bose Road, Kolkata-700 020, India.

Leishmania parasites lack catalase and therefore, their anti-oxidant system hinges primarily upon non protein thiols; accordingly, depletion of thiols could potentially serve as an effective drug target. We have developed a flow cytometry based assay using 5-chloromethyl fluorescein diacetate based upon its selective staining of non protein thiols. Its specificity was confirmed using buthionine sulphoximine (a gamma glutamyl cysteine synthetase inhibitor), diamide (an oxidizing agent of intracellular thiols) and N-ethylmaleimide (a covalent modifier of cysteine residues) as evidenced by reduction in fluorescence; furthermore, restoration of fluorescence by N-acetyl cysteine corroborated specificity of 5-chloromethyl fluorescein diacetate to measure non protein thiols. Differences in basal level of thiols in antimony sensitive and antimony resistant Leishmania field isolates were detected. The depletion of non protein thiols by conventional antileishmanial drugs e.g. antimony and miltefosine was demonstrated. Furthermore, fluorescence was unaffected by depletion of ATP in majority of the strains studied, indicating that 5-chloromethyl fluorescein diacetate is not a substrate for the pump operative in most Leishmania donovani strains. Taken together, measurement of 5-chloromethyl fluorescein diacetate fluorescence is an effective method for monitoring non protein thiols in Leishmania promastigotes.

PMID: 19393240 [PubMed - as supplied by publisher]

6: Mol Biochem Parasitol. 2009 May;165(1):57-66. Epub 2009 Jan 20.Click here to read

Mutational studies reveal lysine 352 on the large subunit is indispensable for catalytic activity of bi-subunit topoisomerase I from Leishmania donovani.

Ganguly A, Sengupta S, Bosedasgupta S, Roy A, Majumder HK.

Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, India.

From the vanadate complex crystal structure of Leishmania donovani topoisomerase I, several amino acid residues have been implicated to be involved in the catalytic reaction. Although several predictions and propositions have been made, the exact role of these amino acids has not yet been clearly demonstrated in vitro. Among these residues, lysine 352 and arginine 314 stand as potential candidates for playing the role of a general acid during the cleavage step. In this study, we have characterized the role of lysine 352 on the large subunit, by site-directed mutagenesis and have tried to identify the general acid that can protonate the 5?-O atom of the leaving strand. Studies with the mutant enzymes reveal that, relaxation activity was severely affected when Lys352 was mutated to arginine or alanine (K352R or K352A). Mutation of Arg314 to Lys (R314K) has very little effect on the relaxation activity. Detailed study reveals that, both cleavage and religation steps are severely affected in case of K352R and K352A and the cleavage religation equilibrium is shifted towards the cleavage. On the contrary, the R314K mutant exhibits only a slightly slower rate of cleavage compared to wild-type enzyme. Cleavage assays with an oligonucleotide containing 5?-bridging phosphorothiolate indicate that Lys352 acts as a general acid in the cleavage step. Altogether, this study establishes the indispensable role of lysine 352 in the catalytic reaction of L. donovani topoisomerase I.

PMID: 19393162 [PubMed - in process]

7: Mol Biochem Parasitol. 2009 May;165(1):48-56. Epub 2009 Jan 20.Click here to read

Leishmania major lacking arginase (ARG) are auxotrophic for polyamines but retain infectivity to susceptible BALB/c mice.

Reguera RM, Balaña-Fouce R, Showalter M, Hickerson S, Beverley SM.

Departamento de Ciencias Biomédicas (INTOXCAL), Facultad de Veterinaria, Universidad de León. Campus de Vegazana s/n 24071-León, Spain.

Polyamines are essential metabolites in eukaryotes participating in a variety of proliferative processes, and in trypanosomatid protozoa play an additional role in the synthesis of the critical thiol trypanothione. Whereas the polyamine biosynthesis arising from l-ornithine has been well studied in protozoa, the metabolic origin(s) of l-ornithine have received less attention. Arginase (EC 3.5.3.1) catalyzes the enzymatic hydrolysis of l-arginine to l-ornithine and urea, and we tested the role of arginase in polyamine synthesis by the generation of an arg(?) knockout in Leishmania major by double targeted gene replacement. This mutant lacked arginase activity and required the nutritional provision of polyamines or l-ornithine for growth. A complemented line (arg(?)/+ARG) expressing arginase from a multi-copy expression vector showed 30-fold elevation of arginase activity, similar polyamine and ornithine levels as the wild-type, and resistance to the inhibitors ?-difluoromethylornithine (DFMO) and N(?)-hydroxy-l-arginine (NOHA). This established that arginase is the major route of polyamine synthesis in promastigotes cultured in vitro. The arg(?) parasites retained the ability to differentiate normally to the infective metacyclic stage, and were able to induce progressive disease following inoculation into susceptible BALB/c mice, albeit less efficiently than WT parasites. These data suggest that the infective amastigote form of Leishmania, which normally resides within an acidified parasitophorous vacuole, can survive in vivo through salvage of host polyamines and/or other molecules, aided by the tendency of acidic compartments to concentrate basic metabolites. This may thus contribute to the relative resistance of Leishmania to ornithine decarboxylase (ODC) inhibitors. The availability of infective, viable, arginase-deficient parasites should prove useful in dissecting the role of l-arginine metabolism in both pro- and anti-parasitic responses involving host nitric oxide synthase, which requires l-arginine to generate NO.

PMID: 19393161 [PubMed - in process]

8: Mol Biochem Parasitol. 2009 May;165(1):32-47. Epub 2009 Jan 15.Click here to read

Whole-genome comparative RNA expression profiling of axenic and intracellular amastigote forms of Leishmania infantum.

Rochette A, Raymond F, Corbeil J, Ouellette M, Papadopoulou B.

Research Centre in Infectious Disease, CHUL Research Centre, CHUQ, 2705 Laurier Blvd., Quebec, Canada G1V 4G2; Department of Medical Biology, Faculty of Medicine, Laval University, Quebec, Canada.

Leishmania parasites cycle between the alimentary tract of a sandfly vector as free-living promastigotes and the acidified phagolysosomes of the vertebrate host macrophage as aflagellated amastigotes. The differentiation process can be mimicked in host-free culture by switching promastigotes (e.g. 25 degrees C, neutral pH) to a phagolysosomal-like environment (e.g. 37 degrees C, acidic pH and 5% CO(2)) for certain, but not all Leishmania species. Axenically grown amastigotes have been shown to share several morphological and biochemical characteristics with macrophage-derived intracellular amastigotes. In this study, we used a DNA oligonucleotide full-genome array to compare global RNA expression profiling of Leishmania infantum axenic amastigotes to intracellular amastigotes derived from infected macrophages. In general, 40% more genes (518 genes vs. 309 genes) were found upregulated in axenic amastigotes compared to intracellular amastigotes. Comparisons in expression profiling between axenic amastigotes and intracellular amastigotes revealed substantial differences in regulated mRNA abundance. Remarkably, among the differentially upregulated transcripts only 12% were common to both amastigote preparations. The major differences between axenic and intracellular amastigotes were observed in metabolic process, especially in fatty acid metabolism, in intracellular transport and membrane vesicular fusion, in proteolysis, in the number and type of protein kinases and RNA binding proteins and in the response to oxidative stress. These findings highlight the importance of the host macrophage in driving the parasite to specific adaptations, which consequently result in highly regulated changes in gene expression.

PMID: 19393160 [PubMed - in process]

9: Clin Microbiol Infect. 2009 Apr 18. [Epub ahead of print]Click here to read

Epidemiology and diagnostics of visceral leishmaniasis in Serbia.

Dakic ZD, Pelemis MR, Stevanovic GD, Poluga JL, Lavadinovic LS, Milosevic IS, Indjic NK, Ofori-Belic IV, Pavlovic MD.

Parasitological Laboratory, Institute for Infectious and Tropical Diseases, Bulevar oslobodjenja, Belgrade, Serbia.

Clin Microbiol InfectAbstract A retrospective epidemiological and diagnostic study of visceral leishmaniasis (VL) was carried out during the period 2001-2007 and included patients suspected of VL who had been diagnosed at the Parasitological Laboratory at the Institute for Infectious and Tropical Diseases, Belgrade. Diagnosis of VL was confirmed by microscopic examination of Giemsa-stained bone marrow (BM) smears. BM smears from 134 patients were examined; 22 cases of VL were diagnosed, the majority of which involved individuals who had been on holiday at the Montenegrian sea coast. The sensitivity of the initial BM smears was inadequate; this required the application of a serological test, adapted for routine use, for the diagnosis of VL.

PMID: 19392902 [PubMed - as supplied by publisher]

10: Trop Med Int Health. 2009 Apr 17. [Epub ahead of print]Click here to read

The poorest of the poor: a poverty appraisal of households affected by visceral leishmaniasis in Bihar, India.

Boelaert M, Meheus F, Sanchez A, Singh SP, Vanlerberghe V, Picado A, Meessen B, Sundar S.

Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium.

Summary Objective To provide data about wealth distribution in visceral leishmanisis (VL)-affected communities compared to that of the general population of Bihar State, India. Methods After extensive disease risk mapping, 16 clusters with high VL transmission were selected in Bihar. An exhaustive census of all households in the clusters was conducted and socio-economic household characteristics were documented by questionnaire. Data on the general Bihar population taken from the National Family Health Survey of India were used for comparison. An asset index was developed based on Principal Components Analysis and the distribution of this asset index for the VL communities was compared with that of the general population of Bihar. Results 83% of households in communities with high VL attack rates belonged to the two lowest quintiles of the Bihar wealth distribution. All socio-economic indicators showed significantly lower wealth for those households. Conclusion Visceral leishmanisis clearly affects the poorest of the poor in India. They are most vulnerable, as this vector-born disease is linked to poor housing and unhealthy habitats. The disease leads the affected households to more destitution because of its impact on household income and wealth. Support for the present VL elimination initiative is important in the fight against poverty.

PMID: 19392741 [PubMed - as supplied by publisher]

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