Wednesday, September 30, 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 12

1: PLoS One. 2009 Sep 29;4(9):e7217.

The trypanosome Rab-related proteins RabX1 and RabX2 play no role in IntraCellular trafficking but may be involved in fly infectivity.

Natesan SK, Peacock L, Leung KF, Matthews KR, Gibson W, Field MC.

Department of Pathology, University of Cambridge, Cambridge, United Kingdom.

BACKGROUND: Rab GTPases constitute the largest subgroup of the Ras superfamily and are primarily involved in vesicle targeting. The full extent of Rab family function is unexplored. Several divergent Rab-like proteins are known but few have been characterized. In Trypanosoma brucei there are sixteen Rab genes, but RabX1, RabX2 and RabX3 are divergent within canonical sequence regions. Where known, trypanosome Rab functions are broadly conserved when orthologous relationships may be robustly established, but specific functions for RabX1, X2 and X3 have yet to be determined. RabX1 and RabX2 originated via tandem duplication and subcellular localization places RabX1 at the endoplasmic reticulum, while RabX2 is at the Golgi complex, suggesting distinct functions. We wished to determine whether RabX1 and RabX2 are involved in vesicle transport or other cellular processes. METHODOLOGY/PRINCIPAL FINDINGS: Using comparative genomics we find that RabX1 and RabX2 are restricted to trypanosomatids. Gene knockout indicates that RabX1 and RabX2 are non-essential. Simultaneous RNAi knockdown of both RabX1 and RabX2, while partial, was also non-lethal and may suggest non-redundant function, consistent with the distinct locations of the proteins. Analysis of the knockout cell lines unexpectedly failed to uncover a defect in exocytosis, endocytosis or in the morphology or location of multiple markers for the endomembrane system, suggesting that neither RabX1 nor RabX2 has a major role in intracellular transport. However, it was apparent that RabX1 and RabX2 knockout cells displayed somewhat enhanced survival within flies. CONCLUSIONS/SIGNIFICANCE: RabX1 and RabX2, two members of the trypanosome Rab subfamily, were shown to have no major detectable role in intracellular transport, despite the localization of each gene product to highly specific endomembrane compartments. These data extend the functional scope of Rab proteins in trypanosomes to include non-canonical roles in differentiation-associated processes in protozoa.

PMID: 19787065 [PubMed - in process]

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2: PLoS Negl Trop Dis. 2009 Sep 29;3(9):e523.

Genotypic Status of the TbAT1/P2 Adenosine Transporter of Trypanosoma brucei gambiense Isolates from Northwestern Uganda following Melarsoprol Withdrawal.

Kazibwe AJ, Nerima B, de Koning HP, Mäser P, Barrett MP, Matovu E.

Division of Infection and Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.

BACKGROUND: The development of arsenical and diamidine resistance in Trypanosoma brucei is associated with loss of drug uptake by the P2 purine transporter as a result of alterations in the corresponding T. brucei adenosine transporter 1 gene (TbAT1). Previously, specific TbAT1 mutant type alleles linked to melarsoprol treatment failure were significantly more prevalent in T. b. gambiense from relapse patients at Omugo health centre in Arua district. Relapse rates of up to 30% prompted a shift from melarsoprol to eflornithine (alpha-difluoromethylornithine, DFMO) as first-line treatment at this centre. The aim of this study was to determine the status of TbAT1 in recent isolates collected from T. b. gambiense sleeping sickness patients from Arua and Moyo districts in Northwestern Uganda after this shift in first-line drug choice. METHODOLOGY AND RESULTS: Blood and cerebrospinal fluids of consenting patients were collected for DNA preparation and subsequent amplification. All of the 105 isolates from Omugo that we successfully analysed by PCR-RFLP possessed the TbAT1 wild type allele. In addition, PCR/RFLP analysis was performed for 74 samples from Moyo, where melarsoprol is still the first line drug; 61 samples displayed the wild genotype while six were mutant and seven had a mixed pattern of both mutant and wild-type TbAT1. The melarsoprol treatment failure rate at Moyo over the same period was nine out of 101 stage II cases that were followed up at least once. Five of the relapse cases harboured mutant TbAT1, one had the wild type, while no amplification was achieved from the remaining three samples. CONCLUSIONS/SIGNIFICANCE: The apparent disappearance of mutant alleles at Omugo may correlate with melarsoprol withdrawal as first-line treatment. Our results suggest that melarsoprol could successfully be reintroduced following a time lag subsequent to its replacement. A field-applicable test to predict melarsoprol treatment outcome and identify patients for whom the drug can still be beneficial is clearly required. This will facilitate cost-effective management of HAT in rural resource-poor settings, given that eflornithine has a much higher logistical requirement for its application.

PMID: 19787038 [PubMed - in process]

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3: Vaccine. 2009 Sep 25. [Epub ahead of print]

Optimized subunit vaccine protects against experimental leishmaniasis.

Bertholet S, Goto Y, Carter L, Bhatia A, Howard RF, Carter D, Coler RN, Vedvick TS, Reed SG.

Infectious Disease Research Institute, 1124 Columbia Street, Suite 400, Seattle, WA 98104, USA.

Development of a protective subunit vaccine against Leishmania spp. depends on antigens and adjuvants that induce appropriate immune responses. We evaluated a second generation polyprotein antigen (Leish-110f) in different adjuvant formulations for immunogenicity and protective efficacy against Leishmania spp. challenges. Vaccine-induced protection was associated with antibody and T cell responses to Leish-110f. CD4 T cells were the source of IFN-gamma, TNF, and IL-2 double- and triple-positive populations. This study establishes the immunogenicity and protective efficacy of the improved Leish-110f subunit vaccine antigen adjuvanted with natural (MPL-SE) or synthetic (EM005) Toll-like receptor 4 agonists.

PMID: 19786136 [PubMed - as supplied by publisher]

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4: Microbes Infect. 2009 Sep 25. [Epub ahead of print]

Sorting of Leishmania-bearing dendritic cells reveals subtle parasite-induced modulation of host-cell gene expression.

Lecoeur H, de La Llave E, Osorio Y Fortéa J, Goyard S, Biasizzo HK, Balazuc AM, Milon G, Prina E, Lang T.

Unité d'Immunophysiologie et Parasitisme Intracellulaire, Département de Parasitologie et Mycologie.

Once in the mouse skin, Leishmania amazonensis amastigotes are hosted by professional mononuclear phagocytes such as dendritic cells (DCs). When monitored after parasite inoculation, the frequency of amastigote-hosting DCs is very low (<1%) in both the skin and skin-draining lymph nodes. Therefore, we designed and validated an efficient procedure to purify live amastigotes-hosting DCs with the objective to facilitate quantitative and qualitative analysis of such rare cells. To this end, a Leishmania amazonensis transgenic parasite expressing DsRed2 fluorescent protein was generated and added to mouse bone marrow-derived DC cultures. Then, a high speed sorting procedure, performed in BSL2 containment, was set up to pick out only DCs hosting live amastigotes. This study reveals, for the first time, a unique transcript pattern from sorted live amastigotes-hosting DCs that would have been undetectable in unsorted samples. It was indeed possible to highlight a significant and coordinated up-regulation of L-arginine transporter and arginase2 transcripts in Leishmania-hosting DCs compared to un-parasitized DCs. These results indicate that arginine catabolism for polyamine generation is dominating over L-arginine catabolism for NO generation. In conclusion, this approach provides a powerful method for further characterisation, of amastigote-hosting DCs in the skin and the skin-draining lymph nodes.

PMID: 19786115 [PubMed - as supplied by publisher]

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5: Clin Infect Dis. 2009 Sep 1;49(5):e52-4.Click here to read LinkOut

An estimate of the burden of Chagas disease in the United States.

Bern C, Montgomery SP.

Division of Parasitic Diseases, National Center for Zoonotic, Vector-Borne and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. CBern@cdc.gov <CBern@cdc.gov>

Chagas disease causes the highest burden of any parasitic disease in the Western hemisphere. By applying published seroprevalence figures to immigrant populations, we estimate that 300,167 individuals with Trypanosoma cruzi infection live in the United States, with 30,000-45,000 cardiomyopathy cases and 63-315 congenital infections annually. T. cruzi causes a substantial disease burden in the United States.

PMID: 19640226 [PubMed - indexed for MEDLINE]

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6: Proteomics. 2009 Jul;9(13):3489-506.Click here to read Click here to read References for this PMC Article, Free in PMC, LinkOut

Phosphoproteomic analysis of the human pathogen Trypanosoma cruzi at the epimastigote stage.

Nakayasu ES, Gaynor MR, Sobreira TJ, Ross JA, Almeida IC.

The Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA.

Trypanosoma cruzi is the etiologic agent of Chagas disease, which affects millions of people in Latin America and has become a public health concern in the United States and areas of Europe. The possibility that kinase inhibitors represent novel anti-parasitic agents is currently being explored. However, fundamental understanding of the cell-signaling networks requires the detailed analysis of the involved phosphorylated proteins. Here, we have performed a comprehensive MS-based phosphorylation mapping of phosphoproteins from T. cruzi epimastigote forms. Our LC-MS/MS, dual-stage fragmentation, and multistage activation analysis has identified 237 phosphopeptides from 119 distinct proteins. Furthermore, 220 phosphorylation sites were unambiguously mapped: 148 on serine, 57 on threonine, and 8 on tyrosine. In addition, immunoprecipitation and Western blotting analysis confirmed the presence of at least seven tyrosine-phosphorylated proteins in T. cruzi. The identified phosphoproteins were subjected to Gene Ontology, InterPro, and BLAST analysis, and categorized based on their role in cell structure, motility, transportation, metabolism, pathogenesis, DNA/RNA/protein turnover, and signaling. Taken together, our phosphoproteomic data provide new insights into the molecular mechanisms governed by protein kinases and phosphatases in T. cruzi. We discuss the potential roles of the identified phosphoproteins in parasite physiology and drug development.

PMID: 19579231 [PubMed - indexed for MEDLINE]

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7: Trends Parasitol. 2009 Jun;25(6):252-5. Epub 2009 May 13.Click here to read LinkOut

Complex interactions in the regulation of trypanosome mitochondrial gene expression.

Koslowsky DJ.

Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.

Trypanosomes undergo extreme physiological changes to adapt to different environments as they cycle between hosts. Adaptation to the different environments has evolved an energy metabolism involving a mitochondrion with an unusual genome. Recently, Aphasizhev and colleagues have identified two new protein complexes, a mitochondrial polyadenylation complex and a guide RNA stabilization complex, that provide novel insights into the coordinated expression of the mitochondrial genome.

PMID: 19443271 [PubMed - indexed for MEDLINE]

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8: J Med Primatol. 2009 Aug;38(4):247-51. Epub 2009 Mar 5.Click here to read LinkOut

Fatal acute Chagas disease in a chimpanzee.

Bommineni YR, Dick EJ Jr, Estep JS, Van de Berg JL, Hubbard GB.

Southwest National Primate Research Center at the Southwest Foundation for Biomedical Research, San Antonio, TX 78245-0549, USA.

BACKGROUND: Chagas disease (CD) or American trypanosomiasis is caused by a hemoflagellate protozoan, Trypanosoma cruzi. This organism has been isolated from more than 100 mammalian species and several insect vectors demonstrating a wide host distribution and low host specificity. METHODS: A 23-year-old male chimpanzee died acutely and a complete necropsy was performed to evaluate gross and microscopic pathologic changes. After observation of trypanosomal amastigotes in the myocardium, PCR and immunohistochemistry was employed to confirm the diagnosis of T. cruzi. RESULTS: Gross findings were consistent with mild congestive heart failure. Microscopic findings included multifocal myocardial necrosis associated with severe lymphocytic to mixed inflammatory infiltrates, edema, and mild chronic interstitial fibrosis. Multifocal intracytoplasmic amastigotes morphologically consistent with T. cruzi were observed in cardiac myofibers. Trypanosoma cruzi was confirmed by PCR and immunohistochemistry. CONCLUSION: We report, to the best of our knowledge, the first fatal spontaneous case of T. cruzi infection in a chimpanzee.

PMID: 19281482 [PubMed - indexed for MEDLINE]

PMCID: PMC2711217 [Available on 2010/08/01]

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9: Vet Res. 2009 Mar-Apr;40(2):26. Epub 2009 Mar 3.Click here to read Click here to read References for this PMC Article, Free in PMC, LinkOut

Trypanosoma cruzi: adaptation to its vectors and its hosts.

Noireau F, Diosque P, Jansen AM.

UR 016, Institut de Recherche pour le Développement (IRD), Montpellier, France. francois.noireau@ird.fr

American trypanosomiasis is a parasitic zoonosis that occurs throughout Latin America. The etiological agent, Trypanosoma cruzi, is able to infect almost all tissues of its mammalian hosts and spreads in the environment in multifarious transmission cycles that may or not be connected. This biological plasticity, which is probably the result of the considerable heterogeneity of the taxon, exemplifies a successful adaptation of a parasite resulting in distinct outcomes of infection and a complex epidemiological pattern. In the 1990s, most endemic countries strengthened national control programs to interrupt the transmission of this parasite to humans. However, many obstacles remain to the effective control of the disease. Current knowledge of the different components involved in elaborate system that is American trypanosomiasis (the protozoan parasite T. cruzi, vectors Triatominae and the many reservoirs of infection), as well as the interactions existing within the system, is still incomplete. The Triatominae probably evolve from predatory reduvids in response to the availability of vertebrate food source. However, the basic mechanisms of adaptation of some of them to artificial ecotopes remain poorly understood. Nevertheless, these adaptations seem to be associated with a behavioral plasticity, a reduction in the genetic repertoire and increasing developmental instability.

PMID: 19250627 [PubMed - indexed for MEDLINE]

PMCID: PMC2695024

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10: Trends Parasitol. 2009 Mar;25(3):132-8. Epub 2009 Feb 4.Click here to read LinkOut

Trypanotolerance in small ruminants of sub-Saharan Africa.

Geerts S, Osaer S, Goossens B, Faye D.

Institute of Tropical Medicine, Animal Health Department, Nationalestraat 155, B-2000 Antwerp, Belgium. sgeerts@itg.be

Although a lot of information is currently available on trypanotolerance in cattle, until recently the trypanotolerant nature of small ruminants was not well known. Trypanotolerance in small ruminants is less pronounced than in cattle and should be considered as resilience rather than resistance. West African Dwarf (WAD) goats seem to be less trypanotolerant than Djallonke sheep. However, recent studies have shown that there is an important introgression of genes of trypanosusceptible breeds into WAD goat populations, which possibly explains the loss of trypanotolerance in these animals. Measures need to be taken to safeguard and upgrade the genetic purity of trypanotolerant goat and sheep breeds in Africa.

PMID: 19200783 [PubMed - indexed for MEDLINE]

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