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 15

1.	Parasitol Res. 2011 Apr 19. [Epub ahead of print] An evolutionary analysis of trypanosomatid GP63 proteases. Ma L, Chen K, Meng Q, Liu Q, Tang P, Hu S, Yu J. CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, No.7 Beitucheng West Road, , Chaoyang District, , Beijing, 100029, People's Republic of China. Abstract The trypanosomatid GP63 proteases are known to be involved in parasite-host interaction and exhibit strong sequence and structural similarities to those of their hosts and insect vectors. Based on genome sequences of the three trypanosomatids, Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp., we annotated all their GP63 proteases and divided highly duplicated T. cruzi GP63 proteases into four novel groups according to sequence features. In Leishmania spp., we studied the evolutionary dynamics of GP63 proteins and identified 57 amino acid sites that are under significant positive selections. These sites may contribute to the functional variations of the GP63 proteases and provide clues for vaccine development.
	PMID: 21503641 [PubMed - as supplied by publisher]
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2.	J Cell Sci. 2011 May 1;124(Pt 9):1496-509. Evolutionary reconstruction of the retromer complex and its function in Trypanosoma brucei. Koumandou VL, Klute MJ, Herman EK, Nunez-Miguel R, Dacks JB, Field MC. Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QT, UK. Abstract Intracellular trafficking and protein sorting are mediated by various protein complexes, with the retromer complex being primarily involved in retrograde traffic from the endosome or lysosome to the Golgi complex. Here, comparative genomics, cell biology and phylogenetics were used to probe the early evolution of retromer and its function. Retromer subunits Vps26, Vps29 and Vps35 are near universal, and, by inference, the complex was an ancient feature of eukaryotic cells. Surprisingly, we found DSCR3, a Vps26 paralogue in humans associated with Down's syndrome, in at least four eukaryotic supergroups, implying a more ancient origin than previously suspected. By contrast, retromer cargo proteins showed considerable interlineage variability, with lineage-specific and broadly conserved examples found. Vps10 trafficking probably represents an ancestral role for the complex. Vps5, the BAR-domain-containing membrane-deformation subunit, was found in diverse eukaryotes, including in the divergent eukaryote Trypanosoma brucei, where it is the first example of a BAR-domain protein. To determine functional conservation, an initial characterisation of retromer was performed in T. brucei; the endosomal localisation and its role in endosomal targeting are conserved. Therefore retromer is identified as a further feature of the sophisticated intracellular trafficking machinery of the last eukaryotic common ancestor, with BAR domains representing a possible third independent mechanism of membrane-deformation arising in early eukaryotes.
	PMID: 21502137 [PubMed - in process]
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3.	Eur J Med Chem. 2011 Mar 31. [Epub ahead of print] Synthesis and antileishmanial activity of novel 5-(5-nitrofuran-2-y1)-1,3,4-thiadiazoles with piperazinyl-linked benzamidine substituents. Tahghighi A, Marznaki FR, Kobarfard F, Dastmalchi S, Mojarrad JS, Razmi S, Ardestani SK, Emami S, Shafiee A, Foroumadi A. Department of Medicinal Chemistry, School of Pharmacy and Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Abstract In order to optimize the antileishmanial activity of piperazinyl-linked 5-(5-nitrofuran-2-yl)-1,3,4-thiadiazoles, we synthesized a series of 5-(5-nitrofuran-2-y1)-1,3,4-thiadiazoles with piperazinyl-linked benzamidine substituent as scaffold found in pentamidine related antiprotozoals. The structure of target compounds was confirmed by IR, (1)H NMR, (13)C NMR and Mass spectral data. All compounds were tested for in vitro activity against the promastigote and amastigote forms of Leishmania major. From the results, we found that the substitution on amidine nitrogen has profound role in the biological activity of these compounds. The 5-nitrofuran-2-yl-1,3,4-thiadiazoles having n-propyl, n-butyl and benzyl side chain on benzamidine (as in compounds 2d, 2e and 2g, respectively) showed very good activity in both forms of promastigote and amastigote. The most active compound was N-propyl-4-(4-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl)piperazin-1-yl) benzamidine hydrochloride (2d) with IC(50) value of 0.08 μM in promastigote model. This compound showed a very low level of toxicity against macrophages (CC(50) = 785 μM), with the highest selectivity index (SI = 78.5) among the tested compounds. Copyright © 2011 Elsevier Masson SAS. All rights reserved.
	PMID: 21501907 [PubMed - as supplied by publisher]
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4.	Cell Host Microbe. 2011 Apr 21;9(4):331-41. Leishmania Repression of Host Translation through mTOR Cleavage Is Required for Parasite Survival and Infection. Jaramillo M, Gomez MA, Larsson O, Shio MT, Topisirovic I, Contreras I, Luxenburg R, Rosenfeld A, Colina R, McMaster RW, Olivier M, Costa-Mattioli M, Sonenberg N. Department of Biochemistry and Goodman Cancer Center, McGill University, Montreal, Quebec H3G 1Y6, Canada. Abstract The protozoan parasite Leishmania alters the activity of its host cell, the macrophage. However, little is known about the effect of Leishmania infection on host protein synthesis. Here, we show that the Leishmania protease GP63 cleaves the mammalian/mechanistic target of rapamycin (mTOR), a serine/threonine kinase that regulates the translational repressor 4E-BP1. mTOR cleavage results in the inhibition of mTOR complex 1 (mTORC1) and concomitant activation of 4E-BP1 to promote Leishmania proliferation. Consistent with these results, pharmacological activation of 4E-BPs with rapamycin, results in a dramatic increase in parasite replication. In contrast, genetic deletion of 4E-BP1/2 reduces parasite load in macrophages ex vivo and decreases susceptibility to cutaneous leishmaniasis in vivo. The parasite resistant phenotype of 4E-BP1/2 double-knockout mice involves an enhanced type I IFN response. This study demonstrates that Leishmania evolved a survival mechanism by activating 4E-BPs, which serve as major targets for host translational control. Copyright © 2011 Elsevier Inc. All rights reserved.
	PMID: 21501832 [PubMed - in process]
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5.	Cell Host Microbe. 2011 Apr 21;9(4):319-30. Imaging host cell-leishmania interaction dynamics implicates parasite motility, lysosome recruitment, and host cell wounding in the infection process. Forestier CL, Machu C, Loussert C, Pescher P, Späth GF. Institut Pasteur, CNRS URA 2581, INSERM AVENIR Program, G5 Virulence Parasitaire, 75015 Paris, France; INSERM, Institut Pasteur, 25-28 Rue du Dr Roux, 75015 Paris, France. Abstract Leishmania donovani causes human visceral leishmaniasis. The parasite infectious cycle comprises extracellular flagellated promastigotes that proliferate inside the insect vector, and intracellular nonmotile amastigotes that multiply within infected host cells. Using primary macrophages infected with virulent metacyclic promastigotes and high spatiotemporal resolution microscopy, we dissect the dynamics of the early infection process. We find that motile promastigotes enter macrophages in a polarized manner through their flagellar tip and are engulfed into host lysosomal compartments. Persistent intracellular flagellar activity leads to reorientation of the parasite flagellum toward the host cell periphery and results in oscillatory parasite movement. The latter is associated with local lysosomal exocytosis and host cell plasma membrane wounding. These findings implicate lysosome recruitment followed by lysosome exocytosis, consistent with parasite-driven host cell injury, as key cellular events in Leishmania host cell infection. This work highlights the role of promastigote polarity and motility during parasite entry. Copyright © 2011 Elsevier Inc. All rights reserved.
	PMID: 21501831 [PubMed - in process]
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6.	Cell Host Microbe. 2011 Apr 21;9(4):310-8. Transmission Stages Dominate Trypanosome Within-Host Dynamics during Chronic Infections. Macgregor P, Savill NJ, Hall D, Matthews KR. Centre for Immunity, Infection, and Evolution, Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JT, UK. Abstract Sleeping sickness is characterized by waves of the extracellular parasite Trypanosoma brucei in host blood, with infections continuing for months or years until inevitable host death. These waves reflect the dynamic conflict between the outgrowth of a succession of parasite antigenic variants and their control by the host immune system. Although a contributor to these dynamics is the density-dependent differentiation from proliferative "slender forms" to transmissible "stumpy forms," an absence of markers discriminating stumpy forms has prevented accurate parameterization of this component. Here, we exploit the stumpy-specific PAD1 marker, which functionally defines transmission competence, to quantitatively monitor stumpy formation during chronic infections. This allows reconstruction of the temporal events early in infection. Mathematical modeling of these data describes the parameters controlling trypanosome within-host dynamics and provides strong support for a quorum-sensing-like mechanism. Our data reveal the dominance of transmission stages throughout infection, a consequence being austere use of the parasite's antigen repertoire. Copyright © 2011 Elsevier Inc. All rights reserved.
	PMID: 21501830 [PubMed - in process]
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7.	Cell Host Microbe. 2011 Apr 21;9(4):257-9. Leishmania Parasites Act as a Trojan Horse that Paralyzes the Translation System of Host Macrophages. Shapira M, Zinoviev A. Department of Life Sciences, Ben Gurion University of the Negev, POB 653, Beer Sheva 84105, Israel. Abstract GP63 is an abundant GPI-anchored surface metalloprotease of Leishmania. Jaramillo et al. (2011) show that GP63 manipulates the translation system of host macrophages by cleaving mTOR, which leads to 4E-BP1 dephosphorylation. This study pioneers the observation that Leishmania parasites metabolically paralyze their host cells using an elegant translation shutoff mechanism. Copyright © 2011 Elsevier Inc. All rights reserved.
	PMID: 21501824 [PubMed - in process]
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8.	Biol Aujourdhui. 2011;205(1):5-28. Epub 2011 Apr 19. [The importance of model organisms to study ci lia and flagella biology.] [Article in French] Vincensini L, Blisnick T, Bastin P. Abstract Cilia and flagella are ubiquitous organelles that protrude from the surfaces of many cells, and whose architecture is highly conserved from protists to humans. These complex organelles, composed of over 500 proteins, can be either immotile or motile. They are involved in a myriad of biological processes, including sensing (non-motile cilia) and/or cell motility or movement of extracellular fluids (motile cilia). The ever-expanding list of human diseases linked to defective cilia illustrates the functional importance of cilia and flagella. These ciliopathies are characterised by an impressive diversity of symptoms and an often complex genetic etiology. A precise knowledge of cilia and flagella biology is thus critical to better understand these pathologies. However, multi-ciliated cells are terminally differentiated and difficult to manipulate, and a primary cilium is assembled only when the cell exits from the cell cycle. In this context the use of model organisms, that relies on the high degree of structural but also of molecular conservation of these organelles across evolution, is instrumental to decipher the many facets of cilia and flagella biology. In this review, we highlight the specific strengths of the main model organisms to investigate the molecular composition, mode of assembly, sensing and motility mechanisms and functions of cilia and flagella. Pioneering studies carried out in the green alga Chlamydomonas established the link between cilia and several genetic diseases. Moreover, multicellular organisms such as mouse, zebrafish, Xenopus, C. elegans or Drosophila, and protists like Paramecium, Tetrahymena and Trypanosoma or Leishmania each bring specific advantages to the study of cilium biology. For example, the function of genes involved in primary ciliary dyskinesia (due to defects in ciliary motility) can be efficiently assessed in trypanosomes. © Société de Biologie, 2011.
	PMID: 21501571 [PubMed - as supplied by publisher]
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9.	Cell Microbiol. 2011 Mar 23. doi: 10.1111/j.1462-5822.2011.01593.x. [Epub ahead of print] Quantitative proteome profiling informs on phenotypic traits that adapt Leishmania donovani for axenic and intracellular proliferation. Pescher P , Blisnick T, Bastin P, Späth GF. Institut Pasteur, CNRS URA 2581, Laboratory of Parasite Virulence and Trypanosome Cell Biology Unit, and the Institut National de la Santé et de la Recherche Médicale (INSERM) AVENIR Program, 75015 Paris, France. Abstract Protozoan parasites of the genus Leishmania are important human pathogens that differentiate inside host macrophages into an amastigote life cycle stage. Although this stage causes the pathogenesis of leishmaniasis, only few proteins have been implicated in amastigote intracellular survival. Here we compare morphology, infectivity, and protein expression of L. donovani LD1S grown in host free (axenic) culture, or exclusively propagated in infected hamsters, with the aim to reveal parasite traits absent in axenic but selected for in hamster-derived amastigotes through leishmanicidal host activities. Axenic and splenic amastigotes showed a striking difference in virulence and the ability to cause experimental hepato-splenomegaly in infected hamsters. 2D-DIGE analysis revealed statistically significant differences in abundance for 152 spots, with 14 spots showing five fold or higher abundance in splenic amastigotes. Proteins identified by MS analysis include the anti-oxidant enzyme tryparedoxin peroxidase, and enzymes implicated in protein and amino acid metabolism. Analysis of parasite growth in vitro in minimal medium demonstrated increased survival of hamster-derived compared to axenic parasites under conditions that mimic the nutrient poor, cytotoxic phagolysosome. Thus, our comparative proteomics analysis sheds important new light on the biochemistry of bona fide amastigotes and informs on survival factors relevant for intracellular L. donovani infection. © 2011 Blackwell Publishing Ltd.
	PMID: 21501362 [PubMed - as supplied by publisher]
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10.	Cell Microbiol. 2011 Apr 18. doi: 10.1111/j.1462-5822.2011.01589.x. [Epub ahead of print] Mammalian antimi crobial peptide influences control of cutaneous Leishmania infection. Kulkarni MM, Barbi J, McMaster WR, Gallo RL, Satoskar AR, McGwire BS. Center for Microbial Interface Biology and Division of Infectious Diseases, The Ohio State University Medical Center, Columbus, Ohio, USA Department of Microbiology, The Ohio State University Medical Center, Columbus, Ohio, USA Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada Division of Dermatology, Dept. of Medicine, University of California San Diego and VA San Diego Medical Center, San Diego, California, USA. Abstract Cathelicidin-type antimicrobial peptides (CAMP) are important mediators of innate immunity against microbial pathogens acting through direct interaction with and disruption of microbial membranes and indirectly through modulation of host cell migration and activation. Using a mouse knock-out model in CAMP we studied the role of this host peptide in control of dissemination of cutaneous infection by the parasitic protozoan Leishmania. The presence of pronounced host inflammatory infiltration in lesions and lymph nodes of infected animals was CAMP-dependent. Lack of CAMP expression was associated with higher levels of IL-10 receptor expression in bone marrow, splenic and lymph node macrophages as well as higher anti-inflammatory IL-10 production by bone marrow macrophages and spleen cells but reduced production of the pro-inflammatory cytokines IL-12 and IFN-γ by lymph nodes. Unlike wildtype mice, local lesions were exacerbated and parasites were found largely disseminated in CAMP knockouts. Infection of CAMP knockouts with parasite mutants lacking the surface-metalloprotease virulence determinant resulted in more robust disseminated infection than in control animals suggesting that CAMP activity is negatively regulated by parasite-surface proteolytic activity. This correlated with the ability of the protease to degrade CAMP in vitro and co-localization of CAMP with parasites within macrophages. Our results highlight the interplay of antimicrobial peptides and Leishmania that influence the host immune response and the outcome of infection. © 2011 Blackwell Publishing Ltd.
	PMID: 21501359 [PubMed - as supplied by publisher]
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