What's new for 'Trypanosomatids' in PubMed

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Sent on Wednesday, 2012 May 09
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 18

1.	PLoS One. 2012;7(5):e36303. Epub 2012 May 2. On the evolution of hexose transporters in kinetoplastid potozoans. Pereira CA, Silber AM. Source Instituto de Investigaciones Médicas "Alfredo Lanari," Ciudad Autónoma de Buenos Aires, Argentina. Abstract Glucose, an almost universally used energy and carbon source, is processed through several well-known metabolic pathways, primarily glycolysis. Glucose uptake is considered to be the first step in glycolysis. In kinetoplastids, a protozoan group that includes relevant human pathogens, the importance of glucose uptake in different phases of the life cycles is well established, and hexose transporters have been proposed as targets for therapeutic drugs. However, little is known about the evolutionary history of these hexose transporters. Hexose transporters contain an intracellular N- and C- termini, and 12 transmembrane spans connected by alternate intracellular and extracellular loops. In the present work we tested the hypothesis that the evolutionary rate of the transmembrane span is different from that of the whole sequence and that it is possible to define evolutionary units inside the sequence. The phylogeny of whole molecules was compared to that of their transmembrane spans and the loops connecting the transmembrane spans. We show that the evolutionary units in these proteins primarily consist of clustered rather than individual transmembrane spans. These analyses demonstrate that there are evolutionary constraints on the organization of these proteins; more specifically, the order of the transmembrane spans along the protein is highly conserved. Finally, we defined a signature sequence for the identification of kinetoplastid hexose transporters.
	PMID: 22567148 [PubMed - in process]

2.	Front Immunol. 2012;3:80. Epub 2012 Apr 17. T helper1/t helper2 cells and resistance/susceptibility to leishmania infection: is this paradigm still relevant? Alexander J, Brombacher F. Source Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde Glasgow, UK. Abstract Work in large part on Leishmania major in the 1980s identified two distinct apparently counter-regulatory CD4(+) T cell populations, T helper (h)1 and Th2, that controlled resistance/susceptibility to infection respectively. However, the generation of IL-4(-/-) mice in the 1990s questioned the paramount role of this Th2 archetypal cytokine in the non-healing response to Leishmania infection. The more recent characterization of CD4(+) T cell regulatory populations and further effector CD4(+) T helper populations, Th17, Th9, and T follicular (f)h cells as well as the acknowledged plasticity in T helper cell function has further added to the complexity of host pathogen interactions. These interactions are complicated by the multiplicity of cells that respond to CD4(+) T cell subset signatory cytokines, as well as the diversity of Leishmania species that are often subject to significantly different immune-regulatory controls. In this article we review current knowledge with regard to the role of CD4(+) T cells and their products during Leishmania infection. In particular we update on our studies using conditional IL-4Rα gene-deficient mice that have allowed dissection of the cell interplay dictating the disease outcomes of the major Leishmania species infecting humans.
	PMID: 22566961 [PubMed - in process]

3.	Front Immunol. 2012;3:69. Epub 2012 Apr 17. Vaccines for canine leishmaniasis. Palatnik-de-Sousa CB. Source Laboratório de Biologia e Bioquímica de Leishmania, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil. Abstract Leishmaniasis is the third most important vector-borne disease worldwide. Visceral leishmaniasis (VL) is a severe and frequently lethal protozoan disease of increasing incidence and severity due to infected human and dog migration, new geographical distribution of the insect due to global warming, coinfection with immunosuppressive diseases, and poverty. The disease is an anthroponosis in India and Central Africa and a canid zoonosis (ZVL) in the Americas, the Middle East, Central Asia, China, and the Mediterranean. The ZVL epidemic has been controlled by one or more measures including the culling of infected dogs, treatment of human cases, and insecticidal treatment of homes and dogs. However, the use of vaccines is considered the most cost-effective control tool for human and canine disease. Since the severity of the disease is related to the generation of T-cell immunosuppression, effective vaccines should be capable of sustaining or enhancing the T-cell immunity. In this review we summarize the clinical and parasitological characteristics of ZVL with special focus on the cellular and humoral canine immune response and review state-of-the-art vaccine development against human and canine VL. Experimental vaccination against leishmaniasis has evolved from the practice of leishmanization with living parasites to vaccination with crude lysates, native parasite extracts to recombinant and DNA vaccination. Although more than 30 defined vaccines have been studied in laboratory models no human formulation has been licensed so far; however three second-generation canine vaccines have already been registered. As expected for a zoonotic disease, the recent preventive vaccination of dogs in Brazil has led to a reduction in the incidence of canine and human disease. The recent identification of several Leishmania proteins with T-cell epitopes anticipates development of a multiprotein vaccine that will be capable of protecting both humans and dogs against VL.
	PMID: 22566950 [PubMed - in process]

4.	Front Immunol. 2012;3:58. Epub 2012 Mar 21. Subversion and Utilization of Host Innate Defense by Leishmania amazonensis. Soong L. Source Center for Tropical Diseases, Sealy Center for Vaccine Development, Department of Microbiology and Immunology, The University of Texas Medical Branch Galveston, TX, USA. Abstract Infection with Leishmania amazonensis and other members of the Leishmania mexicana complex can lead to diverse clinical manifestations, some of which are relatively difficult to control, even with standard chemotherapy. Diffuse cutaneous leishmaniasis (CL) is a rare but severe form, and its clinical hallmark is excessive parasitic growth in infected cells accompanied by profound impairments in host immune responses to the parasites. Since these parasites also cause non-healing CL in most inbred strains of mice, these animals are valuable models for dissecting the mechanisms of persistent infection and disease pathogenesis. In comparison to other Leishmania species, L. amazonensis infections are most remarkable for their ability to repress the activation and effector functions of macrophages, dendritic cells, and CD4(+) T cells, implying discrete mechanisms at work. In addition to this multilateral suppression of host innate and adaptive immunity, the activation of types I and II interferon-mediated responses and autophagic/lipid metabolic pathways actually promotes rather than restrains L. amazonensis infection. These seemingly contradictory findings reflect the remarkable adaptation of the parasites to the ancient defense machinery of the host, as well as the complex parasite-host interactions at different stages of infection, which collectively contribute to non-healing leishmaniasis in the New World. This review article highlights new evidence that reveals the strategies utilized by L. amazonensis parasites to subvert or modulate host innate defense machinery in neutrophils and macrophages, as well as the regulatory roles of host innate responses in promoting parasite survival and replication within the huge parasitophorous vacuoles. A better understanding of unique features in host responses to these parasites at early and late stages of infection is important for the rational design of control strategies for non-healing leishmaniasis.
	PMID: 22566939 [PubMed - in process]

5.	Front Immunol. 2012;3:32. Epub 2012 Feb 27. Does T Helper Differentiation Correlate with Resistance or Susceptibility to Infection with L. major? Some Insights From the Murine Model. Tacchini-Cottier F, Weinkopff T, Launois P. Source Department of Biochemistry, WHO Immunology Research and Training Center, University of Lausanne Epalinges, Switzerland. Abstract The murine model of Leishmania major infection has been an invaluable tool in understanding T helper differentiation in vivo. The initial evidence for a role of distinct CD4(+) T helper subsets in the outcome of infection was first obtained with this experimental model. The development of CD4(+) Th1 cells was associated with resolution of the lesion, control of parasite replication, and resistance to re-infection in most of the mouse strains investigated (i.e., C57BL/6). In contrast, differentiation of CD4(+) Th2 cells correlated with the development of unhealing lesions, and failure to control parasite load in a few strains (i.e., BALB/c). Since these first reports, an incredible amount of effort has been devoted to understanding the various parameters involved in the differentiation of these, and more recently discovered T helper subsets such as Th17 and T regulatory cells. The discovery of cross-talk between T helper subsets, as well as their plasticity force us to reevaluate the events driving a protective/deleterious T helper immune response following infection with L. major in mice. In this review, we describe the individual contributions of each of these CD4(+) T helper subsets following L. major inoculation, emphasizing recent advances in the field, such as the impact of different substrains of L. major on the pathogenesis of disease.
	PMID: 22566916 [PubMed - in process]

6.	Front Immunol. 2012;3:5. Epub 2012 Jan 24. CD8(+) T cells in leishmania infections: friends or foes? Stäger S, Rafati S. Source Institut National de la Recherche Scientifique, Institut Armand Frappier, Université du Québec Laval, QC, Canada. Abstract Host protection against several intracellular pathogens requires the induction of CD8(+) T cell responses. CD8(+) T cells are potent effector cells that can produce high amounts of pro-inflammatory cytokines and kill infected target cells efficiently. However, a protective role for CD8(+) T cells during Leishmania infections is still controversial and largely depends on the infection model. In this review, we discuss the role of CD8(+) T cells during various types of Leishmania infections, following vaccination, and as potential immunotherapeutic targets.
	PMID: 22566891 [PubMed - in process]

7.	PLoS Negl Trop Dis. 2012 May;6(5):e1633. Epub 2012 May 1. Temporal dynamics and impact of climate factors on the incidence of zoonotic cutaneous leishmaniasis in central Tunisia. Toumi A, Chlif S, Bettaieb J, Alaya NB, Boukthir A, Ahmadi ZE, Salah AB. Source Laboratory of Medical Epidemiology, Pasteur Institute of Tunis, Tunis, Tunisia. Abstract BACKGROUND: Old world Zoonotic Cutaneous Leishmaniasis (ZCL) is a vector-borne human disease caused by Leishmania major, a unicellular eukaryotic parasite transmitted by pool blood-feeding sand flies mainly to wild rodents, such as Psammomys obesus. The human beings who share the rodent and sand fly habitats can be subverted as both sand fly blood resource. ZCL is endemic in the Middle East, Central Asia, Subsaharan and North Africa. Like other vector-borne diseases, the incidence of ZCL displayed by humans varies with environmental and climate factors. However, so far no study has addressed the temporal dynamics or the impact of climate factors on the ZCL risk. PRINCIPAL FINDINGS: Seasonality during the same epidemiologic year and interval between ZCL epidemics ranging from 4 to 7 years were demonstrated. Models showed that ZCL incidence is raising i) by 1.8% (95% confidence intervals CI:0.0-3.6%) when there is 1 mm increase in the rainfall lagged by 12 to 14 months ii) by 5.0% (95% CI: 0.8-9.4%) when there is a 1% increase in humidity from July to September in the same epidemiologic year. CONCLUSION/SIGNIFICANCE: Higher rainfall is expected to result in increased density of chenopods, a halophytic plant that constitutes the exclusive food of Psammomys obesus. Consequently, following a high density of Psammomys obesus, the pool of Leishmania major transmissible from the rodents to blood-feeding female sand flies could lead to a higher probability of transmission to humans over the next season. These findings provide the evidence that ZCL is highly influenced by climate factors that could affect both Psammomys obesus and the sand fly population densities.
	PMID: 22563513 [PubMed - in process]

8.	PLoS Negl Trop Dis. 2012 May;6(5):e1629. Epub 2012 May 1. Evaluation of Nephroprotective and Immunomodulatory Activities of Antioxidants in Combination with Cisplatin against Murine Visceral Leishmaniasis. Sharma M, Sehgal R, Kaur S. Source Department of Zoology, Panjab University, Chandigarh, India. Abstract BACKGROUND: Most available drugs against visceral leishmaniasis are toxic, and growing limitations in available chemotherapeutic strategies due to emerging resistant strains and lack of an effective vaccine against visceral leishmaniasis deepens the crisis. Antineoplastic drugs like miltefosine have in the past been effective against the parasitic infections. An antineoplastic drug, cisplatin (cis-diamminedichloroplatinum II; CDDP), is recognized as a DNA-damaging drug which also induces alteration of cell-cycle in both promastigotes and amastigotes leading to cell death. First in vivo reports from our laboratory revealed the leishmanicidal potential of cisplatin. However, high doses of cisplatin produce impairment of kidney, which can be reduced by the administration of antioxidants. METHODOLOGY/PRINCIPAL FINDINGS: The present study was designed to evaluate the antileishmanial effect of cisplatin at higher doses (5 mg and 2.5 mg/kg body weight) and its combination with different antioxidants (vitamin C, vitamin E and silibinin) so as to eliminate the parasite completely and reduce the toxicity. In addition, various immunological, hematological and biochemical changes induced by it in uninfected and Leishmania donovani infected BALB/c mice were investigated. CONCLUSION/SIGNIFICANCE: A significant reduction in parasite load, higher IgG2a and lower IgG1 levels, enhanced DTH responses, and greater concentration of Th1 cytokines (IFN-γ, IL-2) with a concomitant down regulation of IL-10 and IL-4 pointed towards the generation of the protective Th1 type of immune response. A combination of cisplatin with antioxidants resulted in successful reduction of nephrotoxicity by normalizing the enzymatic levels of various liver and kidney function tests. Reduction in parasite load, increase in Th1 type of immune responses, and normalization of various biochemical parameters occurred in animals treated with cisplatin in combination with various antioxidants as compared to those treated with the drug only. The above results are promising as antioxidants reduced the potential toxicity of high doses of cisplatin, making the combination a potential anti-leishmanial therapy, especially in resistant cases.
	PMID: 22563510 [PubMed - in process]

9.	PLoS Negl Trop Dis. 2012 May;6(5):e1618. Epub 2012 May 1. Untargeted Metabolomics Reveals a Lack Of Synergy between Nifurtimox and Eflornithine against Trypanosoma brucei. Vincent IM, Creek DJ, Burgess K, Woods DJ, Burchmore RJ, Barrett MP. Source The Wellcome Trust Centre for Molecular Parasitology, Institute for Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom. Abstract A non-targeted metabolomics-based approach is presented that enables the study of pathways in response to drug action with the aim of defining the mode of action of trypanocides. Eflornithine, a polyamine pathway inhibitor, and nifurtimox, whose mode of action involves its metabolic activation, are currently used in combination as first line treatment against stage 2, CNS-involved, human African trypanosomiasis (HAT). Drug action was assessed using an LC-MS based non-targeted metabolomics approach. Eflornithine revealed the expected changes to the polyamine pathway as well as several unexpected changes that point to pathways and metabolites not previously described in bloodstream form trypanosomes, including a lack of arginase activity and N-acetylated ornithine and putrescine. Nifurtimox was shown to be converted to a trinitrile metabolite indicative of metabolic activation, as well as inducing changes in levels of metabolites involved in carbohydrate and nucleotide metabolism. However, eflornithine and nifurtimox failed to synergise anti-trypanosomal activity in vitro, and the metabolomic changes associated with the combination are the sum of those found in each monotherapy with no indication of additional effects. The study reveals how untargeted metabolomics can yield rapid information on drug targets that could be adapted to any pharmacological situation.
	PMID: 22563508 [PubMed - in process]

10.	Eukaryot Cell. 2012 May 4. [Epub ahead of print] Editosome Accessory Factors KREPB9 and KREPB10 in Trypanosoma brucei. Lerch M, Carnes J, Acestor N, Guo X, Schnaufer A, Stuart K. Source Seattle Biomedical Research Institute, Seattle, WA 98109, USA. Abstract Multiprotein complexes, called editosomes, catalyze the uridine insertion and deletion RNA editing that forms translatable mitochondrial mRNAs in kinetoplastid parasites. We identify here two new U1-like zinc finger proteins that associate with editosomes and show that they are related to KREPB6, KREPB7, and KREPB8 and thus named them Kinetoplastid RNA Editing Proteins, KREPB9 and KREPB10. They are conserved and syntenic in the Trypanosoma, although KREPB10 is absent in T. vivax and both are absent in Leishmania. TAP-tagged KREPB9 and KREPB10 incorporate into ∼20S editosomes and/or subcomplexes thereof and preferentially associate with deletion subcomplexes as do KREPB6, KREPB7 and KREPB8. KREPB10 also associates with editosomes that are isolated via a chimeric endonuclease, KREN1 in KREPB8 RNAi cells, or MEAT1. The purified complexes have pre-cleaved editing activities and endonuclease cleavage activity that appears to leave a 5' OH on the 3' product. RNAi knockdowns did not affect growth, but resulted in relative reductions of both edited and unedited mitochondrial mRNAs. The similarity of KREPB9 and KREPB10 to KREPB6, KREPB7, and KREPB8 suggests they may be accessory factors that affect editing endonuclease activity and as a consequence may affect mitochondrial mRNA stability. KREPB9 and KREPB10, along with KREPB6-8, may enable the endonucleases to discriminate among and accurately cleave hundreds of different editing sites and may be involved in the control of differential editing during the life cycle of T. brucei.
	PMID: 22562468 [PubMed - as supplied by publisher]