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 11

1.	Virchows Arch. 2010 Sep 21. [Epub ahead of print] Murine immune response induced by Leishmania major during the implantation of paraffin tablets. Letícia Costa Reis M, Martins Ferreira V, Zhang X, Gonçalves R, Quércia Vieira L, Luiz Tafuri W, Mosser DM, Luiz Tafuri W. Departamento de Patologia Geral, Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Av Antonio Carlos, Campus Pampulha, Belo Horizonte, 6627, MG, Brazil, marialeticia@ufmg.br. Abstract We carried out a model of chronic inflammation using a subcutaneous paraffin tablet in mice experimentally infected with Leishmania major. It was previously reported that the parasite load following paraffin implantation occurred at a peak of 21 days in both BALB/c and C57BL/6 mice. At the present study, we have investigated what cytokines and chemokines are directly related to the parasite load in C57BL/6 mice. All mice were divided in four groups: mice implanted with paraffin tablets; mice experimentally infected with L. major; mice implanted with paraffin tablets and experimentally infected with L. major; and mice submitted only to the surgery were used for the Real-Time Polymerase Chain Reaction (RT-PCR) controls. Fragments of skin tissue and the tissue surrounding the paraffin tablets (inflammatory capsule) were collected for histopathology and RT-PCR studies. By 21 days, a diffuse chronic inflammatory reaction was mainly observed in the deep dermis where macrophages parasitized with Leishmania amastigotes were also found. RT-PCR analysis has shown that BALB/c mice showed strong IL-4 and IL-10 mRNA expression than controls with very little expression of IFN-γ. In contrast, both IFN-γ and IL-10 mRNA was found in higher levels in C57BL/6 animals. Moreover, in C57BL/6 mice the expression of chemokines mRNA of CCL3/MIP-1α was more highly expressed than CCL2/MCP-1. We conclude that the Th1 immune response C57BL/6 did not change to a Th2 response, even though C57BL/6 animals presented higher parasitism than BALB/c mice 21 days after infection and paraffin implantation.
	PMID: 20857143 [PubMed - as supplied by publisher]
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2.	PLoS Negl Trop Dis. 2010 Sep 14;4(9). pii: e822. Design, Development and Evaluation of rK28-Based Point-of-Care Tests for Improving Rapid Diagnosis of Visceral Leishmaniasis. Pattabhi S, Whittle J, Mohamath R, El-Safi S, Moulton GG, Guderian JA, Colombara D, Abdoon AO, Mukhtar MM, Mondal D, Esfandiari J, Kumar S, Chun P, Reed SG, Bhatia A. Infectious Disease Research Institute, Seattle, Washington, United States of America. Abstract BACKGROUND: Visceral leishmaniasis (VL) is diagnosed by microscopic confirmation of the parasite in bone marrow, spleen or lymph node aspirates. These procedures are unsuitable for rapid diagnosis of VL in field settings. The development of rK39-based rapid diagnostic tests (RDT) revolutionized diagnosis of VL by offering high sensitivity and specificity in detecting disease in the Indian subcontinent; however, these tests have been less reliable in the African subcontinent (sensitivity range of 75-85%, specificity of 70-92%). We have addressed limitations of the rK39 with a new synthetic polyprotein, rK28, followed by development and evaluation of two new rK28-based RDT prototype platforms. METHODOLOGY/PRINCIPAL FINDINGS: Evaluation of 62 VL-confirmed sera from Sudan provided sensitivities of 96.8% and 93.6% (95% CI = K28: 88.83-99.61%; K39: 84.30-98.21%) and specificities of 96.2% and 92.4% (95% CI = K28: 90.53-98.95%; K39: 85.54-96.65%) for rK28 and rK39, respectively. Of greater interest was the observation that individual VL sera with low rK39 reactivity often had much higher rK28 reactivity. This characteristic of the fusion protein was exploited in the development of rK28 rapid tests, which may prove to be crucial in detecting VL among patients with low rK39 antibody levels. Evaluation of two prototype lateral flow-based rK28 rapid tests on 53 VL patients in Sudan and 73 VL patients in Bangladesh provided promisingly high sensitivities (95.9% [95% CI = 88.46-99.1 in Sudan and 98.1% [95% CI = 89.93-99.95%] in Bangladesh) compared to the rK39 RDT (sensitivities of 86.3% [95% CI = 76.25-93.23%] in Sudan and 88.7% [95% CI = 76.97-95.73%] in Bangladesh). CONCLUSIONS/SIGNIFICANCE: Our study compares the diagnostic accuracy of rK39 and rK28 in detecting active VL cases and our findings indicate that rK28 polyprotein has great potential as a serodiagnostic tool. A new rK28-based RDT will prove to be a valuable asset in simplifying VL disease confirmation at the point-of-care.
	PMID: 20856856 [PubMed - as supplied by publisher]
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3.	PLoS Negl Trop Dis. 2010 Sep 14;4(9). pii: e819. Viability and Burden of Leishmania in Extralesional Sites during Human Dermal Leishmaniasis. Romero I, Téllez J, Suárez Y, Cardona M, Figueroa R, Zelazny A, Gore Saravia N. Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Cali, Colombia. Abstract BACKGROUND: The clinical and epidemiological significance of Leishmania DNA in extralesional sites is obscured by uncertainty of whether the DNA derives from viable parasites. To examine dissemination of Leishmania during active disease and the potential participation of human infection in transmission, Leishmania 7SLRNA was exploited to establish viability and estimate parasite burden in extralesional sites of dermal leishmaniasis patients. METHODS: The feasibility of discriminating parasite viability by PCR of Leishmania 7SLRNA was evaluated in relation with luciferase activity of luc transfected intracellular amastigotes in dose-response assays of Glucantime cytotoxicity. Monocytes, tonsil swabs, aspirates of normal skin and lesions of 28 cutaneous and 2 mucocutaneous leishmaniasis patients were screened by kDNA amplification/Southern blot. Positive samples were analyzed by quantitative PCR of Leishmania 7SLRNA genes and transcripts. RESULTS: 7SLRNA amplification coincided with luciferase activity, confirming discrimination of parasite viability. Of 22 patients presenting kDNA in extralesional samples, Leishmania 7SLRNA genes or transcripts were detected in one or more kDNA positive samples in 100% and 73% of patients, respectively. Gene and transcript copy number amplified from extralesional tissues were comparable to lesions. 7SLRNA transcripts were detected in 13/19 (68%) monocyte samples, 5/12 (42%) tonsil swabs, 4/11 (36%) normal skin aspirates, and 22/25 (88%) lesions; genes were quantifiable in 15/19 (79%) monocyte samples, 12/13 (92%) tonsil swabs, 8/11 (73%) normal skin aspirates. CONCLUSION: Viable parasites are present in extralesional sites, including blood monocytes, tonsils and normal skin of dermal leishmaniasis patients. Leishmania 7SLRNA is an informative target for clinical and epidemiologic investigations of human leishmaniasis.
	PMID: 20856851 [PubMed - as supplied by publisher]
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4.	Immunol Cell Biol. 2010 Sep 21. [Epub ahead of print] TGF-β-regulated tyrosine phosphatases induce lymphocyte apoptosis in Leishmania donovani-infecte d hamsters. Banerjee R, Kumar S, Sen A, Mookerjee A, Roy S, Pal S, Das P. Molecular Parasitology, Rajendra memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar, India. Abstract Visceral leishmaniasis, which is caused by Leishmania donovani, is one of the major health problems of the Indian subcontinent. Infected hosts have been reported to have impaired lymphoproliferation. However, the fate of anergic cells is still elusive. In the present investigation, L. donovani-infected hamsters were used to study the mechanism of lymphocyte cell death. Lymph node-derived lymphocytes were analysed for apoptotic death through mitochondrial abnormality, caspase activity and DNA degradation. The data demonstrate that the disease progression leads to a gradual impairment of lymphocyte proliferation in the presence of Concanavalin A. The fate of the anergic lymphocytes is intrinsic apoptosis, which is evident by the depolarization of the mitochondrial membrane potential, cytosolic release of cytochrome c, caspase activation and DNA fragmentation. Tumour growth factor (TGF)-β, which is secreted by macrophages, was significantly upregulated in the lymph node compartment of infected hamsters. Adding a neutralizing TGF-β antibody and a recombinant TGF-β resulted in the downregulation and induction of lymphocyte apoptosis, respectively. Furthermore, it has been observed that TGF-β triggers the apoptotic death of lymphocytes through the upregulation of tyrosine phosphatase activity and that the use of sodium orthovanadate (Na(3)VO(4), a tyrosine phosphatase inhibitor) reduces the apoptotic frequency. Thus, this study clearly reports the novel involvement of tyrosine phosphatases in TGF-β-induced lymphocyte apoptosis in Leishmania-infected hamsters.Immunology and Cell Biology advance online publication, 21 September 2010; doi:10.1038/icb.2010.108.
	PMID: 20856262 [PubMed - as supplied by publisher]
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5.	Antimicrob Agents Chemother. 2010 Sep 20. [Epub ahead of print] Aziridine-2,3-Dicarboxylate-Based Cysteine Cathepsin Inhibitors Induce Cell Death in Leishmania major Associated with Accumulation of Debris in Autophagy-Related Lysosome-Like Vacuoles. Schurigt U, Schad C, Glowa C, Baum U, Thomale K, Schnitzer JK, Schultheis M, Schaschke N, Schirmeister T, Moll H. Institute for Molecular Infection Biology, University of Würzburg, 97080 Würzburg, Germany; Institute of Pharmacy and Food Chemistry, University of Würzburg, 97074 Würzburg, Germany; Faculty of Chemistry, Bielefeld University, 33615 Bielefeld, Germany. Abstract The papain-like cysteine cathepsins expressed by Leishmania play a key role in the life cycle of these parasites, turning them into attractive targets for the development of new drugs. We previously demonstrated that two compounds of a series of peptidomimetic aziridine-2,3-dicarboxylate-based inhibitors, Boc-(S)-Leu-(R)-Pro-(S,S)-Azi(OBn)2 (13b) and Boc-(R)-Leu-(S)-Pro-(S,S)-Azi(OBn)2 (13e), reduced the growth and viability of Leishmania major and the infection rate of macrophages while not showing cytotoxicity against host cells. In the present study, we characterized the mode of action of inhibitors 13b and 13e in L. major. Both compounds targeted leishmanial cathepsin B-like cysteine cathepsin CPC as shown by fluorescence proteinase activity assays and active site labeling with biotin-tagged inhibitors. Furthermore, compounds 13b and 13e were potent inducers of cell death in promastigotes characterized by cell shrinkage, reduction of mitochondrial transmembrane potential, and increased DNA fragmentation. Transmission electron microscopic studies revealed the enrichment of undigested debris in lysosome-like organelles participating in micro- and macroautophagy-like processes. The release of digestive enzymes into the cytoplasm after rupture of membranes of lysosome-like vacuoles resulted in a significant digestion of intracellular compartments. However, plasma membrane integrity of compound-treated promastigotes was maintained for several hours. Taken together, our results suggest that the induction of cell death in Leishmania by cysteine cathepsin inhibitors 13b and 13e is different from mammalian apoptosis and is caused by incomplete digestion in autophagy-related lysosome-like vacuoles.
	PMID: 20855728 [PubMed - as supplied by publisher]
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6.	RNA. 2010 Sep 20. [Epub ahead of print] TbRGG2 facilitates kinetoplastid RNA editing initiation and progression past intrinsic pause sites. Ammerman ML, Presnyak V, Fisk JC, Foda BM, Read LK. Department of Microbiology and Immunology and Witebsky Center for Microbial Pathogenesis and Immunology, University at Buffalo School of Medicine, Buffalo, New York 14214, USA. Abstract TbRGG2 is an essential kinetoplastid RNA editing accessory factor that acts specifically on pan-edited RNAs. To understand the mechanism of TbRGG2 action, we undertook an in-depth analysis of edited RNA populations in TbRGG2 knockdown cells and an in vitro examination of the biochemical activities of the protein. We demonstrate that TbRGG2 down-regulation more severely impacts editing at the 5' ends of pan-edited RNAs than at their 3' ends. The initiation of editing is reduced to some extent in TbRGG2 knockdown cells. In addition, TbRGG2 plays a post-initiation role as editing becomes stalled in TbRGG2-depleted cells, resulting in an overall decrease in the 3' to 5' progression of editing. Detailed analyses of edited RNAs from wild-type and TbRGG2-depleted cells reveal that TbRGG2 facilitates progression of editing past intrinsic pause sites that often correspond to the 3' ends of cognate guide RNAs (gRNAs). In addition, noncanonically edited junction regions are either absent or significantly shortened in TbRGG2-depleted cells, consistent with impaired gRNA transitions. Sequence analysis further suggests that TbRGG2 facilitates complete utilization of certain gRNAs. In vitro RNA annealing and in vivo RNA unwinding assays demonstrate that TbRGG2 can modulate RNA-RNA interactions. Collectively, these data are consistent with a model in which TbRGG2 facilitates initiation and 3' to 5' progression of editing through its ability to affect gRNA utilization, both during the transition between specific gRNAs and during usage of certain gRNAs.
	PMID: 20855539 [PubMed - as supplied by publisher]
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7.	Infect Immun. 2010 Sep 20. [Epub ahead of print] Interleukin-17-Mediated Control of Parasitemia in Experimental Trypanosoma Congolense Infection in Mice. Mou Z< /a>, Jia P, Kuriakose S, Khadem F, Uzonna JE. Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada. Abstract BALB/c mice are highly susceptible to experimental Trypanosome congolense infections, whereas C57BL/6 mice are relatively resistant. Infected highly susceptible BALB/c mice die of systemic inflammatory response syndrome (SIRS). Because IL-17 and Th17 cells regulate inflammatory responses, we investigated their role in the pathogenesis of experimental African trypanosomiasis in mice. Here we show that the production of IL-17 by spleen and liver cells and serum IL-17 level increased after T. congolense infection in mice. Interestingly, infected highly susceptible BALB/c mice produced more IL-17 and had more Th17 cells than infected relatively resistant C57BL/6 mice. Paradoxically, neutralization of IL-17 with anti-IL-17 monoclonal antibody in vivo induced higher parasitemia in both the susceptible and relatively resistant mice. Interestingly, anti-IL-17 antibody-treated mice had higher serum levels of ALT and AST and the production of IL-10 and nitric oxide by liver cells was markedly decreased. Moreover, recombinant IL-17-treated mice exhibited significantly faster parasite control and lower peak parasitemia compared to control mice. Collectively, these results suggest that IL-17/Th17 axis plays a protective role in murine experimental African trypanosomiasis.
	PMID: 20855512 [PubMed - as supplied by publisher]
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8.	Bioorg Chem. 2010 Sep 18. [Epub ahead of print] Efficient synthesis of 16 aromatic Morita-Baylis-Hillman adducts: Biological evaluation on Leishmania amazonensis and Leishmania chagasi. Junior CG, de Assis PA, Silva FP, Sousa SC, de Andrade NG, Barbosa TP, Nerís PL, Segundo LV, Anjos IC, Carvalho GA, Rocha GB, Oliveira MR, Vasconcellos ML. Departamento de Química, Universidade Federal da Paraíba, Campus I, João Pessoa, PB 58059-900, Brazil. Abstract Sixteen aromatic Morita-Baylis-Hillman adducts (MBHA) 1-16 were efficiently synthesized in a one step Morita-Baylis-Hillman reaction (MBHR) involving commercial aldehydes with methyl acrylate or acrylonitrile (81-100% yields) without the formation of side products on DABCO catalysis and at low temperature (0°C). The toxicities of these compounds were assessed against promastigote form of Leishmania amazonensis and Leishmania chagasi. The low synthetic cost of these MBHA, green synthetic protocols, easy one-step synthesis from commercially available and cheap reagents as well as the very good antileishmanial activity obtained for 14 and 16 (IC(50) values of 6.88μgmL(-1) and 11.06μgmL(-1) respectively on L. amazonensis; 9.58μgmL(-1) and 14.34μgmL(-1) respectively on L. chagasi) indicates that these MBHA can be a novel and promising class of anti-parasitic compounds.
	PMID: 20855101 [PubMed - as supplied by publisher]
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9.	Hum Immunol. 2010 Sep 17. [Epub ahead of print] Chemokines and chemokines receptors coordinate the inflammatory immune response in human cutaneous leishmaniasis. Campanelli AP, Brodskyn CI, Boaventura V, Silva C, Roselino AM, Costa J, Saldanha AC, de Freitas LA, de Oliveira CI, Barral-Netto M, Silva JS, Barral A. Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto-University of São Paulo, Ribeirão Preto, SP; Department of Biological Sciences, Bauru Dental School, University of São Paulo, Bauru, São Paulo, Brazil. Abstract Cutaneous Leishmaniasis (CL) includes different clinical manifestations displaying diverse intensity of dermal inflammatory infiltrate. Diffuse CL (DCL) cases are hyporesponsive and lesions show very few lymphocytes and a predominance of macrophages. In contrast, localized CL (LCL) cases are responsive to leishmanial antigen and lesions exhibit granulocytes and mononuclear cell infiltration in its early phases, changing to a pattern with numerous lymphocytes and macrophages later in the lesion. Therefore, different chemokines may affect the predominance of cell infiltration in distinct clinical manifestations. In lesions from LCL patients, we examined by flow cytometry, the presence of different chemokines and their receptors in T cells and we verified a higher expression of CXCR3 in the early stages of LCL (less than 30 days of infection) and a higher expression of CCR4 in the late stages of disease (more than 60 days of infection). We also observed a higher frequency of T cells producing IL-10 in the late stage of LCL. Using immunohistochemistry, we observed a higher expression of CCL7, CCL17 in lesions from late LCL, as well as CCR4 suggesting a preferential recruitment of regulatory T cells in the late LCL. Comparing lesions from LCL and DCL patients, we observed a higher frequency of CCL7 in DCL lesions. These results point out the importance of the chemokines, defining the different types of cells recruited to the site of the infection, which could be related to the outcome of infection as well as the clinical form observed.
	PMID: 20854864 [PubMed - as supplied by publisher]
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10.	Eur J Pharmacol. 2010 Sep 17. [Epub ahead of print] Design and screening of ASIC inhibitors based on aromatic diamidines for combating neurological disorders. Chen X, Orser BA, Macdonald JF. Department of Physiology, University of Toronto, Canada; Robarts Research Institute, University of Western Ontario, Canada. Abstract Acid sensing ion channels (ASICs) are implicated in various brain functions including learning and memory and are involved in a number of neurological disorders such as pain, ischemic stroke, depression, and multiple sclerosis. We have recently defined ASICs as one of receptor targets of aromatic diamidines in neurons. Aromatic diamidines are DNA-binding agents and have long been used in the treatment of leishmaniasis, trypanosomiasis, pneumocystis pneumonia and babesiosis. Moreover, some aromatic diamidines are used as skin-care and baby products and others have potential to suppress tumor growth or to combat malaria. A large number of aromatic diamidines or analogs have been synthesized. Many efforts are being made to optimize the therapeutic spectrum of aromatic diamidines, i.e. to reduce toxicity, increase oral bioavailability and enhance their penetration of the blood-brain-barrier. Aromatic diamidines therefore provide a shortcut of screening for selective ASIC inhibitors with therapeutic potential. Intriguingly nafamostat, a protease inhibitor for treating acute pancreatitis, also inhibits ASIC activities. Aromatic diamidines and nafamostat have many similarities although they belong to distinct classes of medicinal agents for curing different diseases. Here we delineate background, clinical application and drug development of aromatic diamidines that could facilitate the screening for selective ASIC inhibitors for research purposes. Further studies may lead to a drug with therapeutic value and extend the therapeutic scope of aromatic diamidines to combat neurological diseases.
	PMID: 20854810 [PubMed - as supplied by publisher]
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