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Sent on Tuesday, 2011 Jun 28Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| 1. | Eur J Immunol. 2011 Jul;41(7):1817-8. doi: 10.1002/eji.201190041.In this issue.[No authors listed]AbstractCOVER IMAGE: The cover image of this issue is a brightfield microscopy image illustrating the high density of cholesterol crystals accumulating within atherosclerotic plaques of high fat cholesterol diet-fed Apoe(-/-) mice, and is provided by Freigang et al. (pp. 2040-2051). In their article, Freigang et al. identify Nrf2 as the transcription factor that regulates the potent inflammatory response triggered by such crystals. Cholesterol crystals are usually only visible as negative shadows, so-called "clefts", in the conventional staining techniques, whereas here the crystals are directly visualised by in situ fixation, cryosectioning and Oil Red O- and HE-staining. MACROPHAGES: IL-33 RELEASE, TGF-Β CEASE: Colonic phagocytes can promote either tissue destruction or repair depending on the cytokine milieu; however, the cytokines responsible for either of these outcomes remain unclear. Genetic mutations in the TGF-β receptor TGF-βRII have been linked to the development of ulcerative colitis (UC) in humans, but the specific role of TGF-β in macrophage biology in vivo remains obscure. In this issue, Rani et al. generate CD68TGF-β DNRII transgenic mice that lack TGF-β responsive macrophages to address this question. The authors demonstrate a selective defect in the resolution of dextran sodium sulfate-induced colitis in these mice. In addition, CD68TGF-βDNRII mice show a significant delay in goblet cell regeneration, and the colonic macrophages in these mice produce elevated amounts of IL-33, as compared with littermate controls. The defective resolution of colitis seen in CD68TGF-β DNRII mice is also associated with marked colonic eosinophilia. These data, combined with evidence for an association between IL-33 and severe UC, suggest that TGF-β may serve as a critical regulator of IL-33. pp. 2000-2009 NEPHRITIC KIDNEYS: A SOURCE OF LONG-LIVED PLASMA CELLS: The glomerular deposition of autoantibody-autoantigen immune complexes plays a crucial role in the pathogenesis of lupus nephritis, a common manifestation of systemic lupus erythematosus (SLE). To date, little is known about the longevity and antigen-specificity of plasma cells (PCs) in the inflamed kidneys of lupus mice and patients with SLE. In this issue, Starke et al. identify renal short- and long-lived PCs in diseased NZB/W F1 lupus mice; the latter cells being at higher frequency. The authors report that autoantibodies specific for autoantigens such as dsDNA and nucleolin are produced locally within the inflamed kidneys. The authors also show that the frequencies of IgG-secreting PCs directed against nuclear components are increased in the kidneys, as compared with the spleen and bone marrow of the same mice. Altogether, these findings provide novel insights into the pathogenesis of lupus nephritis, and highlight the existence of survival niches for long-lived PCs within inflamed kidneys. pp. 2107-2112 MAST CELLS, DC MATURATION AND UNEXPECTED TH1/TH17 RESPONSES: Mast cells (MCs) are thought to be involved in the regulation of adaptive immune responses through either direct effects on T cells or through modification of antigen-presenting cell functions. To better characterize the underlying mechanisms by which MCs exert their immunoregulatory role, Dudeck et al. investigate the impact of MCs on dendritic cell (DC) function. The authors report a direct crosstalk between mature MCs and immature DCs, leading to DC maturation and DC release of T-cell modulating cytokines. Such MC-"primed" DCs are shown to subsequently induce efficient CD4(+) T-cell proliferation. Surprisingly, the authors report that MC-primed DCs induce CD4(+) T cells to release high levels of IFN-γ and IL-17, suggesting that MCs can promote both Th1 and Th17 responses. In agreement with these in vitro findings, the authors demonstrate that the enhanced disease progression seen in MC-deficient mice during Leishmania major infection correlates with impaired induction of both Th1 and Th17 cells. pp. 1883-1893 ROLE OF NKG2D IN THE ACTIVATION OF INKT CELLS: NKG2D is an important NK-cell activating receptor that allows the targeting of transformed and infected cells expressing the ligands for this receptor, such as MICA. The role of NKG2D expressed on NKT cells, however, remains poorly characterized. In this issue, Kuylenstierna et al. investigate the role of NKG2D in the triggering of cytolytic degranulation in human CD1d-restricted invariant NKT (iNKT) cells. The authors demonstrate that NKG2D plays two roles in iNKT-cell activation: (i) direct activation of NK-like cytolytic activity in the absence of TCR-mediated activation and (ii) co-stimulation in the presence of sub-optimal levels of TCR-mediated activation. These findings underscore the dual nature of NKT cells as effector cells that modulate both innate and adaptive immunity. pp. 1913-1923 TNF: IMMUNOSUPPRESSIVE ACTIONS VIA TREGS: Although counter-intuitive, there is increasing evidence that the pro-inflammatory cytokine TNF can activate immunosuppressive Tregs through TNFR2. In this issue, Hamano et al. further investigate the effects of TNF on Tregs. The authors demonstrate that TNF preferentially up-regulates expression of the co-stimulatory TNF receptor superfamily members TNFR2, 4-1BB and OX40 on Tregs, leading to the proliferation of highly suppressive Tregs. These findings are confirmed in vivo, with the administration of neutralizing anti-TNF Ab blocking both the LPS-induced expansion of splenic Tregs and the up-regulation of TNFR2, OX40 and 4-1BB on those cells in mice. These findings suggest that TNF, OX40L and 4-1BBL, which are known inducers of effector T-cell proinflammatory actions, can also activate Tregs and thereby serve in the dampening of the inflammatory response. pp. 2010-2020. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
| 2. | J Biol Chem. 2011 Jun 25. [Epub ahead of print]PG12, a phospholipid analog with potent antimalarial activity inhibits Plasmodium falciparum CTP:phosphocholine cytidylyltransferase activity.Gonzalez-Bulnes P, Bobenchik AM, Augagneur Y, Cerdam R, Vial H, Llebaria A, Ben Mamoun C.SourceUniversity of Barcelona, Spain; AbstractIn the human malaria parasite Plasmodium falciparum the synthesis of the major and essential membrane phospholipid, phosphatidylcholine, occurs via the CDP-choline and the Serine Decarboxylase Phosphoethanolamine Methylation (SDPM) pathways, which are fueled by host choline, serine and fatty acids. Both pathways share the final two steps catalyzed by two essential enzymes CTP:phosphocholine cytidylyltransferase (PfCCT) and choline-phosphate transferase (PfCEPT). We identified a novel class of phospholipid mimetics, which inhibit the growth of P. falciparum as well as Leishmania and Trypanosoma species. Metabolic analyses showed that one of these compounds, PG12, specifically blocks phosphatidylcholine biosynthesis from both the CDP-choline and SDPM pathways via inhibition of PfCCT. In vitro studies using recombinant PfCCT showed a dose-dependent inhibition of the enzyme by PG12. The potent antimalarial of this compound, its low cytotoxicity profile and its established mode of action make it an excellent lead to advance for further drug development and efficacy in vivo. |
| 3. | Eukaryot Cell. 2011 Jun 24. [Epub ahead of print]Endosomal Localization of the Serum Resistance Associated Protein in African Trypanosomes Confers Human Infectivity.Stephens NA, Hajduk SL.SourceDepartment of Biochemistry and Molecular Biology, University of Georgia, Athens GA 30602. AbstractTrypanosoma brucei rhodesiense is the causative agent of human African sleeping sickness. While the closely related subspecies, T. brucei brucei is highly susceptible to lysis by a subclass of human high density lipoproteins (HDL) called trypanosome lytic factor (TLF), T. b. rhodesiense is resistant and therefore able to establish acute and fatal infections in humans. This resistance is due to expression of the serum resistance associated (SRA) gene, a member of the variant surface glycoprotein (VSG) gene family. Although much has been done to establish the role of SRA in human serum resistance, the specific molecular mechanism of SRA-mediated resistance remains a mystery. Thus, we report the trafficking and steady-state localization of SRA in order to provide more insight into the mechanism of SRA-mediated resistance. We show that SRA traffics to the flagellar pocket of bloodstream form T. brucei, where it localizes transiently before being endocytosed to its steady-state localization in endosomes and demonstrate that the critical point of colocalization between SRA and TLF occurs intracellularly. |
| 4. | J Immunol. 2011 Jun 24. [Epub ahead of print]Uncoupling Protein 2 Negatively Regulates Mitochondrial Reactive Oxygen Species Generation and Induces Phosphatase-Mediated Anti-Inflammatory Response in Experimental Visceral Leishmaniasis.Basu Ball W, Kar S, Mukherjee M, Chande AG, Mukhopadhyaya R, Das PK.SourceMolecular Cell Biology Laboratory, Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata 700 032, India. AbstractTo reside and multiply successfully within the host macrophages, Leishmania parasites impair the generation of reactive oxygen species (ROS), which are a major host defense mechanism against any invading pathogen. Mitochondrial uncoupling proteins are associated with mitochondrial ROS generation, which is the major contributor of total cellular ROS generation. In the present study we have demonstrated that Leishmania donovani infection is associated with strong upregulation of uncoupling protein 2 (UCP2), a negative regulator of mitochondrial ROS generation located at the inner membrane of mitochondria. Functional knockdown of macrophage UCP2 by small interfering RNA-mediated silencing was associated with increased mitochondrial ROS generation, lower parasite survival, and induction of marked proinflammatory cytokine response. Induction of proinflammatory cytokine response in UCP2 knocked-down cells was a direct consequence of p38 and ERK1/2 MAPK activation, which resulted from ROS-mediated inhibition of protein tyrosine phosphatases (PTPs). Administration of ROS quencher, N-acetyl-l-cysteine, abrogated PTP inhibition in UCP2 knocked-down infected cells, implying a role of ROS in inactivating PTP. Short hairpin RNA-mediated in vivo silencing of UCP2 resulted in decreased Src homology 2 domain-containing tyrosine phosphatase 1 and PTP-1B activity and host-protective proinflammatory cytokine response resulting in effective parasite clearance. To our knowledge, this study, for the first time, reveals the induction of host UCP2 expression during Leishmania infection to downregulate mitochondrial ROS generation, thereby possibly preventing ROS-mediated PTP inactivation to suppress macrophage defense mechanisms. |
| 5. | Bioorg Med Chem. 2011 Jun 12. [Epub ahead of print]Convolutamines I and J, antitrypanosomal alkaloids from the bryozoan Amathia tortusa.Davis RA, Sykes M, Avery VM, Camp D, Quinn RJ.SourceEskitis Institute, Griffith University, Brisbane, QLD 4111, Australia. AbstractMass-directed isolation of the CH(2)Cl(2)/CH(3)OH extract from the marine bryozoan Amathia tortusa resulted in the purification of two new brominated alkaloids, convolutamines I (1) and J (2). The structures of 1 and 2 were determined following spectroscopic data analysis. Both compounds were isolated during a drug discovery program aimed at identifying new antitrypanosomal leads from a prefractionated natural product library. Compounds 1 and 2 were shown to be active toward the parasite Trypanosoma brucei brucei with IC(50) values of 1.1 and 13.7μM, respectively. Preliminary toxicity profiling was also performed on both 1 and 2 using the human embryonic kidney cell line, HEK293. Compound 1 was shown to exhibit cytotoxicity against HEK293 with an IC(50) of 22.0μM whilst 2 was inactive at 41.0μM. Copyright © 2011 Elsevier Ltd. All rights reserved. |
| 6. | Methods. 2011 Jun 16. [Epub ahead of print]Leishmania cell-free protein expression system.Kovtun O, Mureev S, Jung WR, Kubala M, Johnston W, Alexandrov K.SourceInstitute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. AbstractCell-free protein expression is an important tool for a rapid production, engineering and labeling of recombinant proteins. However the complex protocols for preparation of eukaryotic cell-free protein expression systems result in high manufacturing costs and limit their utility. Recently we reported a novel cell-free expression system based on the lysate of a fermentable protozoan Leishmania tarentolae. Herein we describe a protocol for high throughput protein expression using Leishmania cell-free lysate. The protocol combines PCR-based synthesis and engineering of translation templates with a combined transcription-translation system. The protocol is adapted to multiwell plate format and allows translation of large protein libraries. In the presented example we translate in vitro and isolate a nearly complete complement of mammalian Rab GTPases. Further applications and developments of the system are discussed. Copyright © 2011 Elsevier Inc. All rights reserved. |
| 7. | Am J Pathol. 2011 Jul;179(1):23-9. Epub 2011 Apr 30.Compartment-Specific Remodeling of Splenic Micro-Architecture during Experimental Visceral Leishmaniasis.Yurdakul P, Dalton J, Beattie L, Brown N, Erguven S, Maroof A, Kaye PM.SourceCentre for Immunology and Infection, Hull York Medical School and Department of Biology, University of York, York, United Kingdom; Department of Microbiology and Clinical Microbiology, Hacettepe University Faculty of Medicine, Sihhiye, Ankara, Turkey. AbstractProgressive splenomegaly is a hallmark of visceral leishmaniasis in humans, canids, and rodents. In experimental murine visceral leishmaniasis, splenomegaly is accompanied by pronounced changes in microarchitecture, including expansion of the red pulp vascular system, neovascularization of the white pulp, and remodeling of the stromal cell populations that define the B-cell and T-cell compartments. Here, we show that Ly6C/G(+) (Gr-1(+)) cells, including neutrophils and inflammatory monocytes, accumulate in the splenic red pulp during infection. Cell depletion using monoclonal antibody against either Ly6C/G(+) (Gr-1; RB6) or Ly6G(+) (1A8) cells increased parasite burden. In contrast, depletion of Ly6C/G(+) cells, but not Ly6G(+) cells, halted the progressive remodeling of Meca-32(+) and CD31(+) red pulp vasculature. Strikingly, neither treatment affected white pulp neovascularization or the remodeling of the fibroblastic reticular cell and follicular dendritic cell networks. These findings demonstrate a previously unrecognized compartment-dependent selectivity to the process of splenic vascular remodeling during experimental murine visceral leishmaniasis, attributable to Ly6C(+) inflammatory monocytes. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
| 8. | Vet Parasitol. 2011 May 27. [Epub ahead of print]Molecular diagnosis of infections and resistance in veterinary and human parasites.Hunt PW.SourceF.D. McMaster Laboratory, CSIRO Livestock Industries, New England Highway,, Locked Mail Bag 1, Armidale, NSW 2350, Australia. AbstractSince 1977, >2000 research papers described attempts to detect, identify and/or quantify parasites, or disease organisms carried by ecto-parasites, using DNA-based tests and 148 reviews of the topic were published. Despite this, only a few DNA-based tests for parasitic diseases are routinely available, and most of these are optional tests used occasionally in disease diagnosis. Malaria, trypanosomiasis, toxoplasmosis, leishmaniasis and cryptosporidiosis diagnosis may be assisted by DNA-based testing in some countries, but there are very few cases where the detection of veterinary parasites is assisted by DNA-based tests. The diagnoses of some bacterial (e.g. lyme disease) and viral diseases (e.g. tick borne encephalitis) which are transmitted by ecto-parasites more commonly use DNA-based tests, and research developing tests for these species makes up almost 20% of the literature. Other important uses of DNA-based tests are for epidemiological and risk assessment, quality control for food and water, forensic diagnosis and in parasite biology research. Some DNA-based tests for water-borne parasites, including Cryptosporidium and Giardia, are used in routine checks of water treatment, but forensic and food-testing applications have not been adopted in routine practice. Biological research, including epidemiological research, makes the widest use of DNA-based diagnostics, delivering enhanced understanding of parasites and guidelines for managing parasitic diseases. Despite the limited uptake of DNA-based tests to date, there is little doubt that they offer great potential to not only detect, identify and quantify parasites, but also to provide further information important for the implementation of parasite control strategies. For example, variant sequences within species of parasites and other organisms can be differentiated by tests in a manner similar to genetic testing in medicine or livestock breeding. If an association between DNA sequence and phenotype has been demonstrated, then qualities such as drug resistance, strain divergence, virulence, and origin of isolates could be inferred by DNA-based tests. No such tests are in clinical or commercial use in parasitology and few tests are available for other organisms. Why have DNA-based tests not had a bigger impact in veterinary and human medicine? To explore this question, technological, biological, economic and sociological factors must be considered. Additionally, a realistic expectation of research progress is needed. DNA-based tests could enhance parasite management in many ways, but patience, persistence and dedication will be needed to achieve this goal. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved. |
| 9. | BMC Genomics. 2011 Mar 7;12:139.Widespread, focal copy number variations (CNV) and whole chromosome aneuploidies in Trypanosoma cruzi strains revealed by array comparative genomic hybridization.Minning TA, Weatherly DB, Flibotte S, Tarleton RL.SourceCenter for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602, USA. AbstractBACKGROUND:Trypanosoma cruzi is a protozoan parasite and the etiologic agent of Chagas disease, an important public health problem in Latin America. T. cruzi is diploid, almost exclusively asexual, and displays an extraordinarily diverse population structure both genetically and phenotypically. Yet, to date the genotypic diversity of T. cruzi and its relationship, if any, to biological diversity have not been studied at the whole genome level. RESULTS:In this study, we used whole genome oligonucleotide tiling arrays to compare gene content in biologically disparate T. cruzi strains by comparative genomic hybridization (CGH). We observed that T. cruzi strains display widespread and focal copy number variations (CNV) and a substantially greater level of diversity than can be adequately defined by the current genetic typing methods. As expected, CNV were particularly frequent in gene family-rich regions containing mucins and trans-sialidases but were also evident in core genes. Gene groups that showed little variation in copy numbers among the strains tested included those encoding protein kinases and ribosomal proteins, suggesting these loci were less permissive to CNV. Moreover, frequent variation in chromosome copy numbers were observed, and chromosome-specific CNV signatures were shared by genetically divergent T. cruzi strains. CONCLUSIONS:The large number of CNV, over 4,000, reported here uphold at a whole genome level the long held paradigm of extraordinary genome plasticity among T. cruzi strains. Moreover, the fact that these heritable markers do not parse T. cruzi strains along the same lines as traditional typing methods is strongly suggestive of genetic exchange playing a major role in T. cruzi population structure and biology. |
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| 10. | Glycoconj J. 2011 Jan;28(1):31-7. Epub 2011 Jan 15.Invasion of Trypanosoma cruzi into host cells is impaired by N-propionylmannosamine and other N-acylmannosamines.Lieke T, Gröbe D, Blanchard V, Grunow D, Tauber R, Zimmermann-Kordmann M, Jacobs T, Reutter W.SourceBernhard-Nocht-Institut für Tropenmedizin, Bernhard-Nocht-Straße 74, 20359, Hamburg, Germany. AbstractThe etiologic agent of Chagas' disease, Trypanosoma cruzi, is widely distributed in South America, affecting millions of people with thousands of deaths every year. Adherence of the infectious trypomastigote to host cells is mediated by sialic acid. T. cruzi cannot synthesize sialic acids on their own but cleave them from the host cells and link them to glycans on the surface of the parasites using the trans-sialidase, a GPI-anchored enzyme. The infectivity of the protozoan parasites strongly depends on the activity of this enzyme. In this report, we investigated whether the transfer of sialic acids from the host to the parasites can be attenuated using novel sialic acid precursors. The cell line 86-HG-39 was infected with T. cruzi and treated with defined N-acylmannosamine analogues bearing an elongated N-acyl side-chain. By treatment of these cells the number of T. cruzi infected cell was reduced up to 60%. We also showed that the activity of the bacterial sialidase C was reduced with N-glycan substrates with elongated N-acyl side chains of the terminal sialic acids. The affinity of this sialidase decreased with the length of the N-acyl side-chain. The data presented suggest that N-acyl modified sialic acid precursors can change the transfer of sialic acids leading to modification of infection. Since the chemotherapy of this disease is inefficient and afflicted by side effects, the need of effective drugs is lasting. These findings propose a new path to prevent the dissemination of T. cruzi in the human hosts. These compounds or further modified analogues might be a basis for the search of new agents against Chagas' disease. |
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