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Sent on Tuesday, 2011 Sep 13Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | PLoS Negl Trop Dis. 2011 Sep;5(9):e1316. Epub 2011 Sep 6.Therapeutic Enhancement of Protective Immunity during Experimental Leishmaniasis.Divanovic S, Trompette A, Ashworth JI, Rao MB, Karp CL.SourceDivision of Molecular Immunology, Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America. AbstractBACKGROUND:Leishmaniasis remains a significant cause of morbidity and mortality in the tropics. Available therapies are problematic due to toxicity, treatment duration and emerging drug resistance. Mouse models of leishmaniasis have demonstrated that disease outcome depends critically on the balance between effector and regulatory CD4(+) T cell responses, something mirrored in descriptive studies of human disease. Recombinant IL-2/diphtheria toxin fusion protein (rIL-2/DTx), a drug that is FDA-approved for the treatment of cutaneous T cell lymphoma, has been reported to deplete regulatory CD4(+) T cells. METHODOLOGY/PRINCIPAL FINDINGS:We investigated the potential efficacy of rIL-2/DTx as adjunctive therapy for experimental infection with Leishmania major. Treatment with rIL-2/DTx suppressed lesional regulatory T cell numbers and was associated with significantly increased antigen-specific IFN-γ production, enhanced lesion resolution and decreased parasite burden. Combined administration of rIL-2/DTx and sodium stibogluconate had additive biological and therapeutic effects, allowing for reduced duration or dose of sodium stibogluconate therapy. CONCLUSIONS/SIGNIFICANCE:These data suggest that pharmacological suppression of immune counterregulation using a commercially available drug originally developed for cancer therapy may have practical therapeutic utility in leishmaniasis. Rational reinvestigation of the efficacy of drugs approved for other indications in experimental models of neglected tropical diseases has promise in providing new candidates to the drug discovery pipeline. |
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| 2. | PLoS Negl Trop Dis. 2011 Sep;5(9):e1308. Epub 2011 Sep 6.Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human african trypanosomiasis.Rodgers J, Jones A, Gibaud S, Bradley B, McCabe C, Barrett MP, Gettinby G, Kennedy PG.SourceInstitute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom. AbstractHuman African trypanosomiasis (HAT), or sleeping sickness, results from infection with the protozoan parasites Trypanosoma brucei (T.b.) gambiense or T.b.rhodesiense and is invariably fatal if untreated. There are 60 million people at risk from the disease throughout sub-Saharan Africa. The infection progresses from the haemolymphatic stage where parasites invade the blood, lymphatics and peripheral organs, to the late encephalitic stage where they enter the central nervous system (CNS) to cause serious neurological disease. The trivalent arsenical drug melarsoprol (Arsobal) is the only currently available treatment for CNS-stage T.b.rhodesiense infection. However, it must be administered intravenously due to the presence of propylene glycol solvent and is associated with numerous adverse reactions. A severe post-treatment reactive encephalopathy occurs in about 10% of treated patients, half of whom die. Thus melarsoprol kills 5% of all patients receiving it. Cyclodextrins have been used to improve the solubility and reduce the toxicity of a wide variety of drugs. We therefore investigated two melarsoprol cyclodextrin inclusion complexes; melarsoprol hydroxypropyl-β-cyclodextrin and melarsoprol randomly-methylated-β-cyclodextrin. We found that these compounds retain trypanocidal properties in vitro and cure CNS-stage murine infections when delivered orally, once per day for 7-days, at a dosage of 0.05 mmol/kg. No overt signs of toxicity were detected. Parasite load within the brain was rapidly reduced following treatment onset and magnetic resonance imaging showed restoration of normal blood-brain barrier integrity on completion of chemotherapy. These findings strongly suggest that complexed melarsoprol could be employed as an oral treatment for CNS-stage HAT, delivering considerable improvements over current parenteral chemotherapy. |
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| 3. | PLoS Negl Trop Dis. 2011 Sep;5(9):e1304. Epub 2011 Sep 6.Metagenomic Analysis of Taxa Associated with Lutzomyia longipalpis, Vector of Visceral Leishmaniasis, Using an Unbiased High-Throughput Approach.McCarthy CB, Diambra LA, Rivera Pomar RV.SourceCentro Regional de Estudios Genómicos, Universidad Nacional de La Plata, Florencio Varela, Buenos Aires, Argentina. AbstractBACKGROUND:Leishmaniasis is one of the most diverse and complex of all vector-borne diseases worldwide. It is caused by parasites of the genus Leishmania, obligate intramacrophage protists characterised by diversity and complexity. Its most severe form is visceral leishmaniasis (VL), a systemic disease that is fatal if left untreated. In Latin America VL is caused by Leishmania infantum chagasi and transmitted by Lutzomyia longipalpis. This phlebotomine sandfly is only found in the New World, from Mexico to Argentina. In South America, migration and urbanisation have largely contributed to the increase of VL as a public health problem. Moreover, the first VL outbreak was recently reported in Argentina, which has already caused 7 deaths and 83 reported cases. METHODOLOGY/PRINCIPAL FINDINGS:An inventory of the microbiota associated with insect vectors, especially of wild specimens, would aid in the development of novel strategies for controlling insect vectors. Given the recent VL outbreak in Argentina and the compelling need to develop appropriate control strategies, this study focused on wild male and female Lu. longipalpis from an Argentine endemic (Posadas, Misiones) and a Brazilian non-endemic (Lapinha Cave, Minas Gerais) VL location. Previous studies on wild and laboratory reared female Lu. longipalpis have described gut bacteria using standard bacteriological methods. In this study, total RNA was extracted from the insects and submitted to high-throughput pyrosequencing. The analysis revealed the presence of sequences from bacteria, fungi, protist parasites, plants and metazoans. CONCLUSIONS/SIGNIFICANCE:This is the first time an unbiased and comprehensive metagenomic approach has been used to survey taxa associated with an infectious disease vector. The identification of gregarines suggested they are a possible efficient control method under natural conditions. Ongoing studies are determining the significance of the associated taxa found in this study in a greater number of adult male and female Lu. longipalpis samples from endemic and non-endemic locations. A particular emphasis is being given to those species involved in the biological control of this vector and to the etiologic agents of animal and plant diseases. |
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| 4. | PLoS Negl Trop Dis. 2011 Sep;5(9):e1295. Epub 2011 Sep 6.In Silico Analysis of Six Known Leishmania major Antigens and In Vitro Evaluation of Specific Epitopes Eliciting HLA-A2 Restricted CD8 T Cell Response.Seyed N, Zahedifard F, Safaiyan S, Gholami E, Doustdari F, Azadmanesh K, Mirzaei M, Saeedi Eslami N, Khadem Sadegh A, Eslami Far A, Sharifi I, Rafati S.SourceMolecular Immunology and Vaccine Research Lab, Pasteur Institute of Iran, Tehran, Iran. AbstractBACKGROUND:As a potent CD8(+) T cell activator, peptide vaccine has found its way in vaccine development against intracellular infections and cancer, but not against leishmaniasis. The first step toward a peptide vaccine is epitope mapping of different proteins according to the most frequent HLA types in a population. METHODS AND FINDINGS:Six Leishmania (L.) major-related candidate antigens (CPB,CPC,LmsTI-1,TSA,LeIF and LPG-3) were screened for potential CD8(+) T cell activating 9-mer epitopes presented by HLA-A*0201 (the most frequent HLA-A allele). Online software including SYFPEITHI, BIMAS, EpiJen, Rankpep, nHLApred, NetCTL and Multipred were used. Peptides were selected only if predicted by almost all programs, according to their predictive scores. Pan-A2 presentation of selected peptides was confirmed by NetMHCPan1.1. Selected peptides were pooled in four peptide groups and the immunogenicity was evaluated by in vitro stimulation and intracellular cytokine assay of PBMCs from HLA-A2(+) individuals recovered from L. major. HLA-A2(-) individuals recovered from L. major and HLA-A2(+) healthy donors were included as control groups. Individual response of HLA-A2(+) recovered volunteers as percent of CD8(+)/IFN-γ(+) T cells after in vitro stimulation against peptide pools II and IV was notably higher than that of HLA-A2(-) recovered individuals. Based on cutoff scores calculated from the response of HLA-A2(-) recovered individuals, 31.6% and 13.3% of HLA-A2(+) recovered persons responded above cutoff in pools II and IV, respectively. ELISpot and ELISA results confirmed flow cytometry analysis. The response of HLA-A2(-) recovered individuals against peptide pools I and III was detected similar and even higher than HLA-A2(+) recovered individuals. CONCLUSION:Using in silico prediction we demonstrated specific response to LmsTI-1 (pool II) and LPG-3- (pool IV) related peptides specifically presented in HLA-A*0201 context. This is among the very few reports mapping L. major epitopes for human HLA types. Studies like this will speed up polytope vaccine idea towards leishmaniasis. |
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| 5. | PLoS Negl Trop Dis. 2011 Sep;5(9):e1287. Epub 2011 Sep 6.Differences between Trypanosoma brucei gambiense Groups 1 and 2 in Their Resistance to Killing by Trypanolytic Factor 1.Capewell P, Veitch NJ, Turner CM, Raper J, Berriman M, Hajduk SL, Macleod A.SourceCollege of Medical, Veterinary and Biological Sciences, Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow, United Kingdom. AbstractBACKGROUND:The three sub-species of Trypanosoma brucei are important pathogens of sub-Saharan Africa. T. b. brucei is unable to infect humans due to sensitivity to trypanosome lytic factors (TLF) 1 and 2 found in human serum. T. b. rhodesiense and T. b. gambiense are able to resist lysis by TLF. There are two distinct sub-groups of T. b. gambiense that differ genetically and by human serum resistance phenotypes. Group 1 T. b. gambiense have an invariant phenotype whereas group 2 show variable resistance. Previous data indicated that group 1 T. b. gambiense are resistant to TLF-1 due in-part to reduced uptake of TLF-1 mediated by reduced expression of the TLF-1 receptor (the haptoglobin-hemoglobin receptor (HpHbR)) gene. Here we investigate if this is also true in group 2 parasites. METHODOLOGY:Isogenic resistant and sensitive group 2 T. b. gambiense were derived and compared to other T. brucei parasites. Both resistant and sensitive lines express the HpHbR gene at similar levels and internalized fluorescently labeled TLF-1 similar fashion to T. b. brucei. Both resistant and sensitive group 2, as well as group 1 T. b. gambiense, internalize recombinant APOL1, but only sensitive group 2 parasites are lysed. CONCLUSIONS:Our data indicate that, despite group 1 T. b. gambiense avoiding TLF-1, it is resistant to the main lytic component, APOL1. Similarly group 2 T. b. gambiense is innately resistant to APOL1, which could be based on the same mechanism. However, group 2 T. b. gambiense variably displays this phenotype and expression does not appear to correlate with a change in expression site or expression of HpHbR. Thus there are differences in the mechanism of human serum resistance between T. b. gambiense groups 1 and 2. |
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| 6. | FASEB J. 2011 Sep 9. [Epub ahead of print]Leishmania ma jor parasite stage-dependent host cell invasion and immune evasion.Wenzel UA, Bank E, Florian C, Förster S, Zimara N, Steinacker J, Klinger M, Reiling N, Ritter U, van Zandbergen G.Source*Institute for Medical Microbiology and Hygiene, University Clinic of Ulm, Ulm, Germany; AbstractLeishmania pathogenesis is primarily studied using the disease-inducing promastigote stage of Leishmania major. Despite many efforts, all attempts so far have failed to culture the disease-relevant multiplying amastigote stage of L. major. Here, we established a stably growing axenic L. major amastigote culture system that was characterized genetically, morphologically, and by stage-specific DsRed protein expression. We found parasite stage-specific disease development in resistant C57BL/6 mice. Human neutrophils, as first host cells for promastigotes, do not take up amastigotes. In human macrophages, we observed an amastigote-specific complement receptor 3-mediated, endocytotic entry mechanism, whereas promastigotes are taken up by complement receptor 1-mediated phagocytosis. Promastigote infection of macrophages induced the inflammatory mediators TNF, CCL3, and CCL4, whereas amastigote infection was silent and resulted in significantly increased parasite numbers: from 7.1 ± 1.4 (after 3 h) to 20.1 ± 7.9 parasites/cell (after 96 h). Our study identifies Leishmania stage-specific disease development, host cell preference, entry mechanism, and immune evasion. Since the amastigote stage is the disease-propagating form found in the infected mammalian host, the newly developed L. major axenic cultures will serve as an important tool in better understanding the amastigote-driven immune response in leishmaniasis.-Wenzel, U. A., Bank, E., Florian, C., Förster, S., Zimara, N., Steinacker, J., Klinger, M., Reiling, N., Ritter, U., van Zandbergen, G. Leishmania major parasite stage-dependent host cell invasion and immune evasion. |
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| 7. | Mol Biochem Parasitol. 2011 Sep 3. [Epub ahead of print]Leishmania donovani encodes a functional enzyme involved in vitamin c biosynthesis: Arabino-1,4-lactone oxidase.Biyani N, Madhubala R.SourceSchool of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India. AbstractPlants and most animals can synthesize ascorbate (vitamin C) for their own requirements, but humans have lost this ability during evolution. The last step in the biosynthesis of l-ascorbic acid involves the conversion of an aldonolactone substrate to ascorbate (or analogues), reactions catalyzed by a family of flavoprotein aldonolactone oxidase/dehydrogenases. We report cloning, molecular characterization, localization and functional importance of arabinonolactone oxidase (LdALO), an enzyme from L. donovani, a protozoan parasite that causes visceral leishmaniasis. L. donovani arabinonolactone oxidase gene is 1509-bp and encodes a putative 502-amino acid protein with a molecular mass of 57-kDa. A 57-kDa protein was obtained by heterologous expression of LdALO in Escherichia coli. Recombinant arabinonolactone oxidase (LdALO) obeys Michaelis-Menten kinetics utilizing d-arabinono-γ-lactone as a substrate, a property characteristic of the yeast enzyme. Activity towards the mammalian substrate, l-gulono-γ-lactone, could not be detected. The inhibitor study profile suggested the essentiality of cysteine residues for the activity of this enzyme. LdALO displayed glycosomal localization as in other kinetoplastids. Overexpression of LdALO in L. donovani resulted in better ability of survival of the parasite within the host in comparison to the vector transfectants. d-Arabinono-γ-lactone oxidase required for synthesizing ascorbate in Leishmania could be considered as a therapeutically exploitable target. Copyright © 2011. Published by Elsevier B.V. |
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| 8. | Mol Biochem Parasitol. 2011 Sep 3. [Epub ahead of print]IMP dehydrogenase deficiency in Leishmania donovani causes a restrictive growth phenotype in promastigotes but is not essential for infection in mice.Fulwiler AL, Boitz JM, Gilroy C, Yates PA, Jardim A, Ullman B.SourceDepartment of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, United States. AbstractLeishmania cannot synthesize purines de novo and therefore must scavenge purines from its host for survival and growth. Biochemical and genomic analyses have indicated that Leishmania species express three potential routes for the synthesis of guanylate nucleotides: (1) a two-step pathway that converts IMP to GMP; (2) a three-step pathway that starts with the deamination of guanine to xanthine, followed by phosphoribosylation to XMP and then conversion to GMP; or (3) direct guanine phosphoribosylation by HGPRT. To determine the role of the first of these pathways to guanylate nucleotide synthesis, an L. donovani line deficient in IMP dehydrogenase (IMPDH), the first step in the IMP to GMP pathway, was constructed by targeted gene replacement. The Δimpdh lesion triggered a highly restrictive growth phenotype in promastigotes in culture but did not impact parasitemias in mice. The dispensability of IMPDH in vivo is the first definitive demonstration that intracellular L. donovani amastigotes have access to a sufficient pool of guanine, xanthine, or guanylate precursors from the host. Copyright © 2011. Published by Elsevier B.V. |
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| 9. | Diagn Microbiol Infect Dis. 2011 Sep 8. [Epub ahead of print]Synthesis, cytotoxicity, and in vitro antileishmanial activity of mono-t-butyloxycarbonyl-protected diamines.Pinheiro AC, Rocha MN, Nogueira PM, Nogueira TC, Jasmim LF, de Souza MV, Soares RP.SourceInstituto de Tecnologia em Fármacos-Far Manguinhos, Fundação Oswaldo Cruz/FIOCRUZ, 21041-250 Rio de Janeiro, RJ, Brazil. AbstractLeishmania amazonensis is the etiologic agent of the cutaneous and diffuse leishmaniasis. This species is often associated with drug resistance, and the conventional treatments exhibit high toxicity for patients. Therefore, the search for new antileishmanial compounds is urgently needed since there is no vaccine available. In this study, using the in vitro traditional drug screening test, we have analyzed the effects of a series of diaminoalkanes monoprotected with t-butyloxycarbonyl (BOC) against L. amazonensis. Among the 18 tested compounds, 6 exhibited antileishmanial activity (2, 7-9, 17, and 18). Best IC(50) values (10.39 ± 0.27 and 3.8 ± 0.42 μg/mL) were observed for compounds 17 and 18 (H(2)N(CH(2))nNHBoc, n = 10 and 12), respectively. Although those compounds had higher lipophilicity as indicated by their cLog P values, compound 17 was very toxic. Determination of the selective indexes indicated that 50% of the active compounds were very toxic for HepG2 cells. However, compounds 2, 8, and 18 had good lipophilicity and were less toxic among all polyamine derivatives tested. The chemical properties of antileishmanial diamine derivatives, such as lipophilicity and cytotoxicity, are relevant factors for the design of new drugs. A higher lipophilicity is likely to improve the chances of reaching this intracellular parasite. Copyright © 2011 Elsevier Inc. All rights reserved. |
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| 10. | Trans R Soc Trop Med Hyg. 2011 Sep 8. [Epub ahead of print]Leishmania species identification using FTA card sampling directly from patients' cutaneous lesions in the state of Lara, Venezuela.Kato H, Watanabe J, Nieto IM, Korenaga M, Hashiguchi Y.SourceLaboratory of Parasitology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan. AbstractA molecular epidemiological study was performed using FTA card materials directly sampled from lesions of patients with cutaneous leishmaniasis (CL) in the state of Lara, Venezuela, where causative agents have been identified as Leishmania (Viannia) braziliensis and L. (Leishmania) venezuelensis in previous studies. Of the 17 patients diagnosed with CL, Leishmania spp. were successfully identified in 16 patients based on analysis of the cytochrome b gene and rRNA internal transcribed spacer sequences. Consistent with previous findings, seven of the patients were infected with L. (V.) braziliensis. However, parasites from the other nine patients were genetically identified as L. (L.) mexicana, which differed from results of previous enzymatic and antigenic analyses. These results strongly suggest that L. (L.) venezuelensis is a variant of L. (L.) mexicana and that the classification of L. (L.) venezuelensis should be reconsidered. Copyright © 2011 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. |
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