What's new for 'Trypanosomatids' in PubMed

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Sent on Friday, 2012 June 22
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 13

1.	PLoS Negl Trop Dis. 2012 Jun;6(6):e1691. Epub 2012 Jun 12. Untreated Human Infections by Trypanosoma brucei gambiense Are Not 100% Fatal. Jamonneau V, Ilboudo H, Kaboré J, Kaba D, Koffi M, Solano P, Garcia A, Courtin D, Laveissière C, Lingue K, Büscher P, Bucheton B. Source Institut de Recherche pour le Développement, Unité Mixte de Recherche IRD-CIRAD 177, Campus International de Baillarguet, Montpellier, France. Abstract The final outcome of infection by Trypanosoma brucei gambiense, the main agent of sleeping sickness, has always been considered as invariably fatal. While scarce and old reports have mentioned cases of self-cure in untreated patients, these studies suffered from the lack of accurate diagnostic tools available at that time. Here, using the most specific and sensitive tools available to date, we report on a long-term follow-up (15 years) of a cohort of 50 human African trypanosomiasis (HAT) patients from the Ivory Coast among whom 11 refused treatment after their initial diagnosis. In 10 out of 11 subjects who continued to refuse treatment despite repeated visits, parasite clearance was observed using both microscopy and polymerase chain reaction (PCR). Most of these subjects (7/10) also displayed decreasing serological responses, becoming progressively negative to trypanosome variable antigens (LiTat 1.3, 1.5 and 1.6). Hence, in addition to the "classic" lethal outcome of HAT, we show that alternative natural progressions of HAT may occur: progression to an apparently aparasitaemic and asymptomatic infection associated with strong long-lasting serological responses and progression to an apparently spontaneous resolution of infection (with negative results in parasitological tests and PCR) associated with a progressive drop in antibody titres as observed in treated cases. While this study does not precisely estimate the frequency of the alternative courses for this infection, it is noteworthy that in the field national control programs encounter a significant proportion of subjects displaying positive serologic test results but negative results in parasitological testing. These findings demonstrate that a number of these subjects display such infection courses. From our point of view, recognising that trypanotolerance exists in humans, as is now widely accepted for animals, is a major step forward for future research in the field of HAT.
	PMID: 22720107 [PubMed - in process]
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2.	PLoS Negl Trop Dis. 2012 Jun;6(6):e1684. Epub 2012 Jun 12. Local increase of arginase activity in lesions of patients with cutaneous leishmaniasis in ethiopia. Abebe T, Hailu A, Woldeyes M, Mekonen W, Bilcha K , Cloke T, Fry L, Seich Al Basatena NK, Corware K, Modolell M, Munder M, Tacchini-Cottier F, Müller I, Kropf P. Source Department of Microbiology, Immunology and Parasitology, Addis Ababa University, Addis Ababa, Ethiopia. Abstract BACKGROUND: Cutaneous leishmaniasis is a vector-borne disease that is in Ethiopia mainly caused by the parasite Leishmania aethiopica. This neglected tropical disease is common in rural areas and causes serious morbidity. Persistent nonhealing cutaneous leishmaniasis has been associated with poor T cell mediated responses; however, the underlying mechanisms are not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We have recently shown in an experimental model of cutaneous leishmaniasis that arginase-induced L-arginine metabolism suppresses antigen-specific T cell responses at the site of pathology, but not in the periphery. To test whether these results translate to human disease, we recruited patients presenting with localized lesions of cutaneous leishmaniasis and assessed the levels of arginase activity in cells isolated from peripheral blood and from skin biopsies. Arginase activity was similar in peripheral blood mononuclear cells (PBMCs) from patients and healthy controls. In sharp contrast, arginase activity was significantly increased in lesion biopsies of patients with localized cutaneous leishmaniasis as compared with controls. Furthermore, we found that the expression levels of CD3ζ, CD4 and CD8 molecules were considerably lower at the site of pathology as compared to those observed in paired PBMCs. CONCLUSION: Our results suggest that increased arginase in lesions of patients with cutaneous leishmaniasis might play a role in the pathogenesis of the disease by impairing T cell effector functions.
	PMID: 22720104 [PubMed - in process]
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3.	PLoS Negl Trop Dis. 2012 Jun;6(6):e1682. Epub 2012 Jun 12. Identification of Mimotopes with Diagnostic Potential for Trypanosoma brucei gambiense Variant Surface Glycoproteins Using Human Antibody Fractions. Van Nieuwenhove L, Büscher P, Balharbi F, Humbert M, Dieltjens T, Guisez Y, Lejon V. Source Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium. Abstract BACKGROUND: At present, screening of the population at risk for gambiense human African trypanosomiasis (HAT) is based on detection of antibodies against native variant surface glycoproteins (VSGs) of Trypanosoma brucei (T.b.) gambiense. Drawbacks of these native VSGs include culture of infective T.b. gambiense trypanosomes in laboratory rodents, necessary for production, and the exposure of non-specific epitopes that may cause cross-reactions. We therefore aimed at identifying peptides that mimic epitopes, hence called "mimotopes," specific to T.b. gambiense VSGs and that may replace the native proteins in antibody detection tests. METHODOLOGY/PRINCIPAL FINDINGS: A Ph.D.-12 peptide phage display library was screened with polyclonal antibodies from patient sera, previously affinity purified on VSG LiTat 1.3 or LiTat 1.5. The peptide sequences were derived from the DNA sequence of the selected phages and synthesised as biotinylated peptides. Respectively, eighteen and twenty different mimotopes were identified for VSG LiTat 1.3 and LiTat 1.5, of which six and five were retained for assessment of their diagnostic performance. Based on alignment of the peptide sequences on the original protein sequence of VSG LiTat 1.3 and 1.5, three additional peptides were synthesised. We evaluated the diagnostic performance of the synthetic peptides in indirect ELISA with 102 sera from HAT patients and 102 endemic negative controls. All mimotopes had areas under the curve (AUCs) of ≥0.85, indicating their diagnostic potential. One peptide corresponding to the VSG LiTat 1.3 protein sequence also had an AUC of ≥0.85, while the peptide based on the sequence of VSG LiTat 1.5 had an AUC of only 0.79. CONCLUSIONS/SIGNIFICANCE: We delivered the proof of principle that mimotopes for T.b. gambiense VSGs, with diagnostic potential, can be selected by phage display using polyclonal human antibodies.
	PMID: 22720103 [PubMed - in process]
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4.	PLoS Negl Trop Dis. 2012 Jun;6(6):e1671. Epub 2012 Jun 12. An Image-Based High-Content Screening Assay for Compounds Targeting Intracellular Leishmania donovani Amastigotes in Human Macrophages. Siqueira-Neto JL, Moon S, Jang J, Yang G, Lee C, Moon HK, Chatelain E, Genovesio A, Cechetto J, Freitas-Junior LH. Source Center for Neglected Diseases Drug Discovery (CND3), Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, South Korea. Abstract Leishmaniasis is a tropical disease threatening 350 million people from endemic regions. The available drugs for treatment are inadequate, with limitations such as serious side effects, parasite resistance or high cost. Driven by this need for new drugs, we developed a high-content, high-throughput image-based screening assay targeting the intracellular amastigote stage of different species of Leishmania in infected human macrophages. The in vitro infection protocol was adapted to a 384-well-plate format, enabling acquisition of a large amount of readouts by automated confocal microscopy. The reading method was based on DNA staining and required the development of a customized algorithm to analyze the images, which enabled the use of non-modified parasites. The automated analysis generated parameters used to quantify compound activity, including infection ratio as well as the number of intracellular amastigote parasites and yielded cytotoxicity information based on the number of host cells. Comparison of this assay with one that used the promastigote form to screen 26,500 compounds showed that 50% of the hits selected against the intracellular amastigote were not selected in the promastigote screening. These data corroborate the idea that the intracellular amastigote form of the parasite is the most appropriate to be used in primary screening assay for Leishmania.
	PMID: 22720099 [PubMed - in process]
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5.	PLoS Negl Trop Dis. 2012 Jun;6(6):e1656. Epub 2012 Jun 12. Prediction score for antimony treatment failure in patients with ulcerative leishmaniasis lesions. Valencia C, Arévalo J, Dujardin JC, Llanos-Cuentas A, Chappuis F, Zimic M. Source Instituto de Medicina Tropical ″Alexander von Humboldt,″ Universidad Peruana Cayetano Heredia (UPCH), Lima, Peru. Abstract BACKGROUND: Increased rates for failure in leishmaniasis antimony treatment have been recently recognized worldwide. Although several risk factors have been identified there is no clinical score to predict antimony therapy failure of cutaneous leishmaniasis. METHODS: A case control study was conducted in Peru from 2001 to 2004. 171 patients were treated with pentavalent antimony and followed up to at least 6 months to determine cure or failure. Only patients with ulcerative cutaneous leishmaniasis (N = 87) were considered for data analysis. Epidemiological, demographical, clinical and laboratory data were analyzed to identify risk factors for treatment failure. Two prognostic scores for antimonial treatment failure were tested for sensitivity and specificity to predict antimony therapy failure by comparison with treatment outcome. RESULTS: Among 87 antimony-treated patients, 18 (21%) failed the treatment and 69 (79%) were cured. A novel risk factor for treatment failure was identified: presence of concomitant distant lesions. Patients presenting concomitant-distant lesions showed a 30.5-fold increase in the risk of treatment failure compared to other patients. The best prognostic score for antimonial treatment failure showed a sensitivity of 77.78% and specificity of 95.52% to predict antimony therapy failure. CONCLUSIONS: A prognostic score including a novel risk factor was able to predict antimonial treatment failure in cutaneous leishmaniasis with high specificity and sensitivity. This prognostic score presents practical advantages as it relies on clinical and epidemiological characteristics, easily obtained by physicians or health workers, and makes it a promising clinical tool that needs to be validated before their use for developing countries.
	PMID: 22720098 [PubMed - in process]
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6.	PLoS Pathog. 2012 Jun;8(6):e1002676. Epub 2012 Jun 14. Manipulation of costimulatory molecules by intracellular pathogens: veni, vidi, vici!! Khan N, Gowthaman U, Pahari S, Agrewala JN. Source CSIR-Institute of Microbial Technology, Chandigarh, India. Abstract Some of the most successful pathogens of human, such as Mycobacterium tuberculosis (Mtb), HIV, and Leishmania donovani not only establish chronic infections but also remain a grave global threat. These pathogens have developed innovative strategies to evade immune responses such as antigenic shift and drift, interference with antigen processing/presentation, subversion of phagocytosis, induction of immune regulatory pathways, and manipulation of the costimulatory molecules. Costimulatory molecules expressed on the surface of various cells play a decisive role in the initiation and sustenance of immunity. Exploitation of the "code of conduct" of costimulation pathways provides evolutionary incentive to the pathogens and thereby abates the functioning of the immune system. Here we review how Mtb, HIV, Leishmania sp., and other pathogens manipulate costimulatory molecules to establish chronic infection. Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells. This review summarizes the convergent devices that pathogens employ to tune and tame the immune system using costimulatory molecules. Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens. We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens.
	PMID: 22719245 [PubMed - in process]
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7.	J Biol Chem. 2012 Jun 20. [Epub ahead of print] Cloning, expression and characterisation of a novel molecular motor, Leishmania myosin-XXI. Batters C, Woodall KA, Toseland CP, Hundschell C, Veigel C . Source Ludwig-Maximilians-Universitaet Muenchen, Germany. Abstract The genome of the Leishmania parasite contains two classes of myosin. Myosin-XXI, seemingly the only myosin isoform expressed in the protozoan parasite, has been detected in both the promastigote and amastigote stages of the Leishmania life cycle. It has been suggested to perform a variety of functions, including roles in membrane anchorage, but also long-range directed movements of cargo. However, nothing is known about the biochemical or mechanical properties of this motor. Here we designed and expressed various myosin-XXI constructs using a baculovirus expression system. Both full-length (aa1-1051) and minimal-motor-domain constructs (aa1-800) featured actin-activated ATPase activity. Myosin-XXI was soluble when expressed either with or without calmodulin. In presence of calcium (pCa 4.1) the full-length motor could bind a single calmodulin at its neck domain (probably aa809-823). Calmodulin-binding was required for motility, but not for ATPase activity. Once bound, calmodulin remained stably attached, independent of calcium concentration (pCa 3-7). In gliding filament assays myosin-XXI moved actin filaments at ~15 nm.s-1, insensitive to both salt (25-1000 mM KCl) and calcium concentrations (pCa 3-7). Calmodulin-binding to the neck domain might be involved in regulating the motility of the myosin-XXI motor for its various cellular functions in the different stages of the Leishmania parasite life cycle.
	PMID: 22718767 [PubMed - as supplied by publisher]
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8.	Parasitology. 2012 May 1:1-13. [Epub ahead of print] Tomatidine promotes the inhibition of 24-alkylated sterol biosynthesis and mitochondrial dysfunction in Leishmania amazonensis promastigotes. Medina JM, Rodrigues JC, DE Souza W, Atella GC, Barrabin H. Source Instituto de Bioquímica Médica, UFRJ, Rio de Janeiro, Brasil. Abstract SUMMARYLeishmaniasis is a set of clinically distinct infectious diseases caused by Leishmania, a genus of flagellated protozoan parasites, that affects ∼12 million people worldwide, with ∼2 million new infections annually. Plants are known to produce substances to defend themselves against pathogens and predators. In the genus Lycopersicon, which includes the tomato, L. esculentum, the main antimicrobial compound is the steroidal glycoalkaloid α-tomatine. The loss of the saccharide side-chain of tomatine yields the aglycone tomatidine. In the present study, we investigated the effects of tomatidine on the growth, mitochondrial membrane potential, sterol metabolism, and ultrastructure of Leishmania amazonensis promastigotes. Tomatidine (0·1 to 5 μM) inhibited parasite growth in a dose-dependent manner (IC50=124±59 nM). Transmission electron microscopy revealed lesions in the mitochondrial ultrastructure and the presence of large vacuoles and lipid storage bodies in the cytoplasm. These structural changes in the mitochondria were accompanied by an effective loss of mitochondrial membrane potential and a decrease in ATP levels. An analysis of the neutral lipid content revealed a large depletion of endogenous 24-alkylated sterols such as 24-methylene-cholesta-5, 7-dien-3β-ol (5-dehydroepisterol), with a concomitant accumulation of cholesta-8, 24-dien-3β-ol (zymosterol), which implied a perturbation in the cellular lipid content. These results are consistent with an inhibition of 24-sterol methyltransferase, an important enzyme responsible for the methylation of sterols at the 24 position, which is an essential step in the production of ergosterol and other 24-methyl sterols.
	PMID: 22716777 [PubMed - as supplied by publisher]
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9.	APMIS. 2012 Jul;120(7):591-6. doi: 10.1111/j.1600-0463.2012.02875.x. Epub 2012 Mar 15. Increased detection of cutaneous leishmaniasis in Norway by use of polymerase chain reaction. Blonski KM, Blödorn-Schlicht N, Falk TM, Faye RS, Clausen OP. Source Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway.
	PMID: 22716214 [PubMed - in process]
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10.	J Proteome Res. 2012 Jun 20. [Epub ahead of print] Analysis of membrane-enriched and high molecular weight proteins in Leishmania infantum promastigotes and axenic amastigotes. Brotherton MC, Racine G, Ahmed Ouameur A, Leprohon P, Papadopoulou B, Ouellette M. Abstract Membrane and high molecular weight (HMW) proteins tend to be underrepresented in proteome analyses. Here, we optimised a protocol designed for the extraction and purification of membranes from the protozoan parasite Leishmania using a combination of serial centrifugation and free-flow zone electrophoresis (ZE-FFE). We also enriched for Leishmania HMW proteins from total extracts using the Gelfree 8100 fractionation system. This allowed the study of expression of both membrane-enriched and HMW proteins in L. infantum promastigotes and amastigotes. We identified 194 proteins with at least one transmembrane domain (TMD) and 171 HMW proteins (≥ 100 kDa) in the invertebrate promastigote stage and 66 proteins with at least one TMD and 154 HMW proteins in the mammalian amastigote stage. Several of the proteins identified in one of the stages are part of pathways consistent with the known biology of the parasite, with many proteins involved in lipid synthesis, numerous dynein heavy chains, and some surface antigen proteins 2 detected in the promastigote stage. Notably, some proteins involved in transport and proteolysis were detected either in promastigote or amastigote. The present study is using improved proteomic methods for studying membrane-enriched and HMW proteins helping to achieve a better understanding of the parasite life cycle.
	PMID: 22716046 [PubMed - as supplied by publisher]
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