What's new for 'Trypanosomatids' in PubMed

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Sent on Saturday, 2012 June 23
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):e1708. Epub 2012 Jun 19. Transcript Expression Analysis of Putative Trypanosoma brucei GPI-Anchored Surface Proteins during Development in the Tsetse and Mammalian Hosts. Savage AF, Cerqueira GC, Regmi S, Wu Y, El Sayed NM, Aksoy S. Source Division of Epidemiology of Microbial Diseases, Yale School of Public Health, Yale University, New Haven, Connecticut, United States of America. Abstract Human African Trypanosomiasis is a devastating disease caused by the parasite Trypanosoma brucei. Trypanosomes live extracellularly in both the tsetse fly and the mammal. Trypanosome surface proteins can directly interact with the host environment, allowing parasites to effectively establish and maintain infections. Glycosylphosphatidylinositol (GPI) anchoring is a common posttranslational modification associated with eukaryotic surface proteins. In T. brucei, three GPI-anchored major surface proteins have been identified: variant surface glycoproteins (VSGs), procyclic acidic repetitive protein (PARP or procyclins), and brucei alanine rich proteins (BARP). The objective of this study was to select genes encoding predicted GPI-anchored proteins with unknown function(s) from the T. brucei genome and characterize the expression profile of a subset during cyclical development in the tsetse and mammalian hosts. An initial in silico screen of putative T. brucei proteins by Big PI algorithm identified 163 predicted GPI-anchored proteins, 106 of which had no known functions. Application of a second GPI-anchor prediction algorithm (FragAnchor), signal peptide and trans-membrane domain prediction software resulted in the identification of 25 putative hypothetical proteins. Eighty-one gene products with hypothetical functions were analyzed for stage-regulated expression using semi-quantitative RT-PCR. The expression of most of these genes were found to be upregulated in trypanosomes infecting tsetse salivary gland and proventriculus tissues, and 38% were specifically expressed only by parasites infecting salivary gland tissues. Transcripts for all of the genes specifically expressed in salivary glands were also detected in mammalian infective metacyclic trypomastigotes, suggesting a possible role for these putative proteins in invasion and/or establishment processes in the mammalian host. These results represent the first large-scale report of the differential expression of unknown genes encoding predicted T. brucei surface proteins during the complete developmental cycle. This knowledge may form the foundation for the development of future novel transmission blocking strategies against metacyclic parasites.
	PMID: 22724039 [PubMed - in process]
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2.	PLoS Negl Trop Dis. 2012 Jun;6(6):e1703. Epub 2012 Jun 19. Evidence for Involvement of Th17 Type Responses in Post Kala Azar Dermal Leishmaniasis (PKDL). Katara GK, Ansari NA, Singh A, Ramesh V, Salotra P . Source National Institute of Pathology (ICMR), Safdarjung Hospital Campus, New Delhi, India. Abstract BACKGROUND: Post kala-azar dermal leishmaniasis (PKDL), a dermal sequel of visceral leishmaniasis, caused by Leishmania donovani, constitutes an important reservoir for the parasite. Parallel functioning of counter acting immune responses (Th1/Th2) reflects a complex immunological scenario, suggesting the involvement of additional regulatory molecules in the disease pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, human cytokine/chemokine/receptor specific cDNA array technique was employed to identify modulations in gene expression of host immuno-determinants during PKDL, followed by evaluation of Th17 type responses by analyzing mRNA and protein expression of Th17 markers (IL-23, IL-17, RORγt) and performing functional assays using Leishmania antigen (TSLA) or recombinant (rec)IL-17. Array analysis identified key immuno-regulatory molecules including cytokines (TNF-α, IFN-γ, IL-10, IL-17), chemokines (MCP-1, MIP-1α), apoptotic molecules (FasL, TRAIL, IRF-1) and receptors (CD40, Fas). Up regulation in lesional expression of Th17 markers was observed during PKDL compared to control (IL-17 and IL-23, P = 0.0008; RORγt, P = 0.02). In follow-up samples, chemotherapy significantly down regulated expression of all markers. In addition, lesional expression of IL-17 was confirmed at protein level by Immuno-histochemistry. Further, systemic presence of Th17 responses (IL-17 and IL-23) was observed in plasma samples from PKDL patients. In functional assays, TSLA stimulated the secretion of IL-17 and IL-23 from PBMCs of PKDL patients, while recIL-17 enhanced the production of TNF-α as well as nitric oxide (NO) in PKDL compared to control (TNF-α, P = 0.0002; NO, P = 0.0013). Further, a positive correlation was evident between lesional mRNA expression of IL-17 and TNF-α during PKDL. CONCLUSION/SIGNIFICANCE: The results highlight key immune modulators in PKDL and provide evidence for the involvement of Th17 type responses in the disease pathogenesis.
	PMID: 22724038 [PubMed - in process]
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3.	PLoS Negl Trop Dis. 2012 Jun;6(6):e1700. Epub 2012 Jun 19. First molecular epidemiological study of cutaneous leishmaniasis in libya. Amro A, Gashout A, Al-Dwibe H, Zahangir Alam M, Annajar B, Hamarsheh O, Shubar H, Schönian G. Source Faculty of Pharmacy, Al-Quds University, Abu-Dies, Jerusalem, Palestine. Abstract BACKGROUND: Cutaneous leishmaniasis (CL) is a major public health problem in Libya. The objective of this study was to investigate, for the first time, epidemiological features of CL outbreaks in Libya including molecular identification of parasites, the geographical distribution of cases and possible scenarios of parasite transmission. METHODOLOGY/PRINCIPAL FINDINGS: We studied 450 patients that came from 49 areas distributed in 12 districts in north-west Libya. The patients' ages ranged from 9 months to 87 years (median age 25 years); 54% of the cases were males. Skin scrapings spotted on glass slides were collected for molecular identification of causative agent. The ribosomal internal transcribed spacer 1 (ITS1) was amplified and subsequently characterized by restriction fragment length polymorphism (RFLP) analysis. In total, 195 samples were successfully identified of which 148 (75.9%) were Leishmania major, and 47 (24.1%) Leishmania tropica. CL cases infected with L. major were found in all CL areas whereas L. tropica cases came mainly from Al Jabal Al Gharbi (46.4%), Misrata (17.8%) and Tarhuna districts (10.7%). A trend of seasonality was noticed for the infections with L. major which showed a clear peak between November and January, but was less pronounced for infections by L. tropica. CONCLUSION: The first molecular study on CL in Libya revealed that the disease is caused by L. major and L. tropica and the epidemiological patterns in the different foci were the same as in other Mediterranean foci of CL.
	PMID: 22724036 [PubMed - in process]
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4.	PLoS Negl Trop Dis. 2012 Jun;6(6):e1687. Epub 2012 Jun 19. Immunodominant Antigens of Leishmania chagasi Associated with Protection against Human Visceral Leishmaniasis. Abánades DR, Arruda LV, Arruda ES, Pinto JR, Palma MS, Aquino D, Caldas AJ, Soto M, Barral A, Barral-Netto M. Source Centro de Pesquisas Gonçalo Moniz (CPqGM), Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brazil. Abstract BACKGROUND: Protection and recovery from visceral leishmaniasis (VL) have been associated with cell-mediated immune (CMI) responses, whereas no protective role has been attributed to humoral responses against specific parasitic antigens. In this report, we compared carefully selected groups of individuals with distinct responses to Leishmania chagasi to explore antigen-recognizing IgG present in resistant individuals. METHODOLOGY AND PRINCIPAL FINDINGS: VL patients with negative delayed-type hypersensitivity (DTH) were classified into the susceptible group. Individuals who had recovered from VL and converted to a DTH+ response, as well as asymptomatic infected individuals (DTH+), were categorized into the resistant group. Sera from these groups were used to detect antigens from L. chagasi by conventional and 2D Western blot assays. Despite an overall reduction in the reactivity of several proteins after DTH conversion, a specific group of proteins (approximately 110-130 kDa) consistently reacted with sera from DTH converters. Other antigens that specifically reacted with sera from DTH+ individuals were isolated and tandem mass spectrometry followed by database query with the protein search engine MASCO were used to identify antigens. The serological properties of recombinant version of the selected antigens were tested by ELISA. Sera from asymptomatic infected people (DTH+) reacted more strongly with a mixture of selected recombinant antigens than with total soluble Leishmania antigen (SLA), with less cross-reactivity against Chagas disease patients' sera. SIGNIFICANCE: Our results are the first evidence of leishmania proteins that are specifically recognized by sera from individuals who are putatively resistant to VL. In addition, these data highlight the possibility of using specific proteins in serological tests for the identification of asymptomatic infected individuals.
	PMID: 22724032 [PubMed - in process]
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5.	PLoS Negl Trop Dis. 2012 Jun;6(6):e1683. Epub 2012 Jun 19. Use of a LiESP/QA-21 Vaccine (CaniLeish) Stimulates an Appropriate Th1-Dominated Cell-Mediated Immune Response in Dogs. Moreno J, Vouldoukis I, Martin V, McGahie D, Cuisinier AM, Gueguen S. Source WHO Collaborating Centre for Leishmaniasis, Centro Nacional de Microbiologia, Instituto de Carlos III, Madrid, Spain. Abstract Canine leishmaniasis is an important zoonotic disease of dogs. The clinical outcome of infection is variable, with the efficiency of the immune response being the key determining factor. There is now a general consensus that a predominant Th1 immune profile in an overall mixed Th1/Th2 response is associated with resistance in dogs, and the absence of a strong Th1 influence is associated with a progression to clinical disease. As a result, there has been a growing demand for vaccines that can induce a specific, strong Th1 response. In this study, we measured the impact of a primary course of a newly available LiESP/QA-21 vaccine on selected humoral and cellular markers of the canine immune response during the onset of immunity. All vaccinated dogs developed a humoral response characterised by IgG2 production. More importantly, vaccinated dogs developed significantly stronger cell-mediated immunity responses than did control dogs. Vaccination induced specific cellular reactivity to soluble Leishmania antigens, with a Leishmania-specific lymphoproliferation (p = 0.0072), characterised by an increased population of T lymphocytes producing IFN-γ (p = 0.0021) and a significant ability of macrophages to reduce intracellular parasite burdens in vitro after co-culture with autologous lymphocytes (p = 0.0014). These responses were correlated with induction of the NOS pathway and production of NO derivatives, which has been shown to be an important leishmanicidal mechanism. These results confirm that vaccination with LiESP/QA-21 induces an appropriate Th1-profile cell-mediated response within three weeks of completing the primary course, and that this response effectively reduces the parasite load in pre-infected macrophages in vitro.
	PMID: 22724031 [PubMed - in process]
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6.	PLoS Negl Trop Dis. 2012 Jun;6(6):e1674. Epub 2012 Jun 19. Sodium Stibogluconate (SSG) & Paromomycin Combination Compared to SSG for Visceral Leishmaniasis in East Africa: A Randomised Controlled Trial. Musa A, Khalil E, Hailu A, Olobo J, Balasegaram M, Omollo R, Edwards T, Rashid J, Mbui J, Musa B, Abuzaid AA, Ahmed O, Fadlalla A, El-Hassan A, Mueller M, Mucee G, Njoroge S, Manduku V, Mutuma G, Apadet L, Lodenyo H, Mutea D, Kirigi G, Yifru S , Mengistu G, Hurissa Z, Hailu W, Weldegebreal T, Tafes H, Mekonnen Y, Makonnen E, Ndegwa S, Sagaki P, Kimutai R, Kesusu J, Owiti R, Ellis S, Wasunna M. Source Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan. Abstract BACKGROUND: Alternative treatments for visceral leishmaniasis (VL) are required in East Africa. Paromomycin sulphate (PM) has been shown to be efficacious for VL treatment in India. METHODS: A multi-centre randomized-controlled trial (RCT) to compare efficacy and safety of PM (20 mg/kg/day for 21 days) and PM plus sodium stibogluconate (SSG) combination (PM, 15 mg/kg/day and SSG, 20 mg/kg/day for 17 days) with SSG (20 mg/kg/day for 30 days) for treatment of VL in East Africa. Patients aged 4-60 years with parasitologically confirmed VL were enrolled, excluding patients with contraindications. Primary and secondary efficacy outcomes were parasite clearance at 6-months follow-up and end of treatment, respectively. Safety was assessed mainly using adverse event (AE) data. FINDINGS: The PM versus SSG comparison enrolled 205 patients per arm with primary efficacy data available for 198 and 200 patients respectively. The SSG & PM versus SSG comparison enrolled 381 and 386 patients per arm respectively, with primary efficacy data available for 359 patients per arm. In Intention-to-Treat complete-case analyses, the efficacy of PM was significantly lower than SSG (84.3% versus 94.1%, difference = 9.7%, 95% confidence interval, CI: 3.6 to 15.7%, p = 0.002). The efficacy of SSG & PM was comparable to SSG (91.4% versus 93.9%, difference = 2.5%, 95% CI: -1.3 to 6.3%, p = 0.198). End of treatment efficacy results were very similar. There were no apparent differences in the safety profile of the three treatment regimens. CONCLUSION: The 17 day SSG & PM combination treatment had a good safety profile and was similar in efficacy to the standard 30 day SSG treatment, suggesting suitability for VL treatment in East Africa. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.govNCT00255567.
	PMID: 22724029 [PubMed - in process]
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7.	Front Immunol. 2012;3:163. Epub 2012 Jun 19. FasL and TRAIL signaling in the skin during cutaneous leishmaniasis - implications for tissue immunopathology and infectious control. Rethi B, Eidsmo L. Source Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. Abstract Cutaneous leishmaniasis (CL) is associated with chronic inflammation and ulceration of the skin. Tissue macrophages serve as host cells and immune activation is necessary for parasite clearance. The balance between immune-mediated tissue destruction and successful clearance of infection is delicate and ulceration has been proposed to be a result of infiltration of activated immune cells into the skin. FasL and TRAIL play a dual role in skin homeostasis through induction of apoptosis as well as proinflammatory signaling. During leishmaniasis, dysregulation of both FasL and TRAIL has been described by us and others but the resulting pathogenic effects in the skin during human leishmaniasis are not fully elucidated. Targeting disease specific immune deviations has proven to be a promising new approach for the therapy of autoimmune diseases. Potentially, targeting FasL or TRAIL in combination with microcidals could offer a future treatment strategy to reduce the disfiguring immunopathology associated with CL. In this mini review we will discuss how FasL and TRAIL-induced signaling may influence on the extent of tissue inflammation and the efficacy of parasite clearance in leishmaniasis.
	PMID: 22723798 [PubMed - in process]
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8.	Ann Dermatol Venereol. 2012 Jun;139(6-7):452-8. Epub 2012 May 31. [Comparative characterization of skin lesions observed in the three endemic varieties of cutaneous leishmaniasis in Tunisia]. [Article in French] Aoun K, Ben Abda I, Bousslimi N, Bettaieb J, Siala E, Ben Abdallah R, Benmously R, Bouratbine A. Source Laboratoire de recherche « parasitoses médicales, biotechnologie & biomolécules » LR 11 IPT 06, institut Pasteur de Tunis, 13, place Pasteur, BP 74, 1002 Tunis Belvédère, Tunisie; Service de parasitologie-mycologie, institut Pasteur de Tunis, 13, place Pasteur, BP 74, 1002 Tunis Belvédère, Tunisie. Abstract BACKGROUND: The recent spread in the geographical distribution of the three forms of cutaneous leishmaniasis (CL) endemic in Tunisia has resulted in the coexistence of more than one species of Leishmania (L.) in some foci, rendering characterization on the basis of geographical criteria alone more difficult. The aim of the study was to establish clinical criteria associated with these noso-geographic forms, namely sporadic CL (SCL) due to L. infantum, zoonotic CL (ZCL) due to L. major and chronic CL (CCL) due to L. tropica. PATIENTS AND METHODS: One hundred and twelve patients with biologically confirmed CL were involved in the study. Leishmania species was systematically identified by iso-enzyme analysis and/or PCR-RFLP. Details of the number, the location, the morphological aspect and the month of outbreak of the lesions were noted for each patient. RESULTS: SCL lesions appeared later than ZCL lesions (53.8% of cases appeared from December onwards vs. 23.6%, P<0.001). ZCL lesions were often multiple (75%) and situated on the limbs (84.7%, P<0.001), whereas SCL lesions were single (92.3%, P<0.001) and located on the face (84.6%, P<0.001). CCL lesions were also single (78.6%) and located on the face (71.4%). The classical ulcerous presentation with scabs was mainly observed in ZCL patients (69.4%) and the erythematous presentation was described more frequently in SCL patients (75%; P<0.001). CONCLUSION: The number, site, morphological aspect and month of outbreak of lesions could be considered as useful criteria that help differentiate between the three noso-geographical forms of CL prevailing in Tunisia. Such characterization is useful for the individual management of patients and for optimizing the combat against the disease. Copyright © 2012 Elsevier Masson SAS. All rights reserved.
	PMID: 22721477 [PubMed - in process]
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9.	J Med Chem. 2012 Jun 21. [Epub ahead of print] Urea-based inhibitors of Trypanosoma brucei methionyl-tRNA synthetase: selectivity and in vivo characterization. Shibata S, Gillespie JR, Ranade RM, Koh CY, Kim JE, Laydbak JU, Zucker FH, Hol WG, Verlinde CL, Buckner FS, Fan E. Abstract Urea-based methionyl-tRNA synthetase inhibitors were designed, synthesized and evaluated for their potential towards treating human African trypanosomiasis (HAT). With the aid of a homology model and a structure-activity-relationship approach, low nM inhibitors were discovered that show high selectivity towards the parasite enzyme over the closest human homolog. These compounds inhibit parasite growth with EC50 values as low as 0.15 μM while having low toxicity to mammalian cells. Two compounds (2 and 26) showed excellent membrane permeation in the MDR1-MDCKII model, and encouraging oral pharmacokinetic properties in mice. Compound 2 was confirmed to enter the CNS in mice. Compound 26 had modest suppressive activity against T. brucei rhodesiense in the mouse model, suggesting that more potent analogs or compounds with higher exposures need to be developed. The urea-based inhibitors are thus a promising starting point for further optimization towards the discovery of orally available and CNS active drugs to treat HAT.
	PMID: 22720744 [PubMed - as supplied by publisher]
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10.	Curr Biol. 2012 Jun 19;22(12):R481-2. Response to zarsky et Al. Pusnik M, Schmidt O, Perry AJ, Oeljeklaus S, Niemann M, Warscheid B, Meisinger C, Lithgow T, Schneider A. Source Department of Chemistry and Biochemistry, University of Bern, CH-3012 Bern, Switzerland. Abstract Mitochondria evolved from an α-proteobacterial endosymbiont and recent phylogenetic and function-based research has demonstrated that the major pieces of the protein transport machinery were inherited from the symbiont. This includes the SAM machinery for assembly of outer membrane proteins and the TIM machinery for protein transport across, and assembly into, the mitochondrial inner membrane [1-3]. Hidden Markov model (HMM) analysis, which enables a broad, all-encompassing approach for identifying protein homologies, has been very important in detecting members of protein families that are not easily recognized by simple BLAST-based comparisons [1]; HMM searches initially failed to find a Tom40 protein in one group of eukaryotes, the kinetoplastids. These organisms, which include the experimentally-tractable Trypanosoma brucei, have highly developed mitochondria that have evolved from the same ancestor as mitochondria in other eukaryotes. The initial failure to identify a Tom40 homolog in T. brucei was both surprising and exciting. Copyright © 2012 Elsevier Ltd. All rights reserved.
	PMID: 22720678 [PubMed - in process]
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