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Sent on Thursday, 2011 Nov 03Search 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 One. 2011;6(10):e26660. Epub 2011 Oct 27.Paromomycin Affects Translation and Vesicle-Mediated Trafficking as Revealed by Proteomics of Paromomycin -Susceptible -Resistant Leishmania donovani.Chawla B, Jhingran A, Panigrahi A, Stuart KD, Madhubala R.SourceSchool of Life Sciences, Jawaharlal Nehru University, New Delhi, India. AbstractLeishmania donovani is a protozoan parasite that causes visceral leishmaniasis (VL) and is responsible for significant mortality and morbidity. Increasing resistance towards antimonial drugs poses a great challenge in chemotherapy of VL. Paromomycin is an aminoglycosidic antibiotic and is one of the drugs currently being used in the chemotherapy of cutaneous and visceral leishmaniasis. To understand the mode of action of this antibiotic at the molecular level, we have investigated the global proteome differences between the wild type AG83 strain and a paromomycin resistant (PRr) strain of L. donovani. Stable isotope labeling of amino acids in cell culture (SILAC) followed by quantitative mass spectrometry of the wild type AG83 strain and the paromomycin resistant (PRr) strain identified a total of 226 proteins at ≥95% confidence. Data analysis revealed upregulation of 29 proteins and down-regulation of 21 proteins in the PRr strain. Comparative proteomic analysis of the wild type and the paromomycin resistant strains showed upregulation of the ribosomal proteins in the resistant strain indicating role in translation. Elevated levels of glycolytic enzymes and stress proteins were also observed in the PRr strain. Most importantly, we observed upregulation of proteins that may have a role in intracellular survival and vesicular trafficking in the PRr strain. Furthermore, ultra-structural analysis by electron microscopy demonstrated increased number of vesicular vacuoles in PRr strain when compared to the wild-type strain. Drug affinity pull-down assay followed by mass spectrometery identified proteins in L. donovani wild type strain that were specifically and covalently bound to paromomycin. These results provide the first comprehensive insight into the mode of action and underlying mechanism of resistance to paromomycin in Leishmania donovani. |
| 2. | PLoS One. 2011;6(10):e26395. Epub 2011 Oct 27.Non-Invasive Cytology Brush PCR Diagnostic Testing in Mucosal Leishmaniasis: Superior Performance to Conventional Biopsy with Histopathology.Boggild AK, Valencia BM, Veland N, Pilar Ramos A, Calderon F, Arevalo J, Low DE, Llanos-Cuentas A.SourceTropical Disease Unit, Division of Infectious Diseases, Toronto General Hospital, University of Toronto, Toronto, Canada. AbstractBACKGROUND:Traditional methods of diagnosing mucosal leishmaniasis (ML), such as biopsy with histopathology, are insensitive and require collection of an invasive diagnostic specimen. METHODS:We compared standard invasive procedures including biopsy histopathology, biopsy PCR, and leishmanin skin test (LST) to a novel, non-invasive, cytology-brush based PCR for the diagnosis of ML in Lima, Peru. Consensus reference standard was 2/4 tests positive, and outcome measures were sensitivity and specificity. Leishmania species identification was performed by PCR-based assays of positive specimens. RESULTS:Twenty-eight patients were enrolled, 23 of whom fulfilled criteria for a diagnosis of ML. Sensitivity and specificity of biopsy with histopathology were 21.7% [95% CI 4.9-38.5%] and 100%; 69.6% [95% CI 50.8-88.4%] and 100% for LST; 95.7% [95% CI 87.4-100%] and 100% for biopsy PCR; and 95.7% [95% CI 87.4-100%] and 90% [95% CI 71.4-100%] for cytology brush PCR using both Cervisoft® and Histobrush® cervical cytology brushes. Represented species identified by PCR-RFLP included: L. (V). braziliensis (n = 4), and L. (V). peruviana (n = 3). CONCLUSIONS:Use of commercial grade cytology brush PCR for diagnosis of ML is sensitive, rapid, well tolerated, and carries none of the risks of invasive diagnostic procedures such as biopsy. Further optimization is required for adequate species identification. Further evaluation of this method in field and other settings is warranted. |
| 3. | PLoS Pathog. 2011 Oct;7(10):e1002340. Epub 2011 Oct 27.Targeting Cattle-Borne Zoonoses and Cattle Pathogens Using a Novel Trypanosomatid-Based Delivery System.Mott GA, Wilson R, Fernando A, Robinson A, Macgregor P, Kennedy D, Schaap D, Matthews JB, Matthews KR.SourceCentre for Immunity, Infection and Evolution, Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom. AbstractTrypanosomatid parasites are notorious for the human diseases they cause throughout Africa and South America. However, non-pathogenic trypanosomatids are also found worldwide, infecting a wide range of hosts. One example is Trypanosoma (Megatrypanum) theileri, a ubiquitous protozoan commensal of bovids, which is distributed globally. Exploiting knowledge of pathogenic trypanosomatids, we have developed Trypanosoma theileri as a novel vehicle to deliver vaccine antigens and other proteins to cattle. Conditions for the growth and transfection of T. theileri have been optimised and expressed heterologous proteins targeted for secretion or specific localisation at the cell interior or surface using trafficking signals from Trypanosoma brucei. In cattle, the engineered vehicle could establish in the context of a pre-existing natural T. theileri population, was maintained long-term and generated specific immune responses to an expressed Babesia antigen at protective levels. Building on several decades of basic research into trypanosomatid pathogens, Trypanosoma theileri offers significant potential to target multiple infections, including major cattle-borne zoonoses such as Escherichia coli, Salmonella spp., Brucella abortus and Mycobacterium spp. It also has the potential to deliver therapeutics to cattle, including the lytic factor that protects humans from cattle trypanosomiasis. This could alleviate poverty by protecting indigenous African cattle from African trypanosomiasis. |
| 4. | PLoS Pathog. 2011 Oct;7(10):e1002325. Epub 2011 Oct 27.Leishmania Mitochondrial Peroxiredoxin Plays a Crucial Peroxidase-Unrelated Role during Infection: Insight into Its Novel Chaperone Activity.Castro H, Teixeira F, Romao S, Santos M, Cruz T, Flórido M, Appelberg R, Oliveira P, Ferreira-da-Silva F, Tomás AM.SourceIBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. AbstractTwo-cysteine peroxiredoxins are ubiquitous peroxidases that play various functions in cells. In Leishmania and related trypanosomatids, which lack catalase and selenium-glutathione peroxidases, the discovery of this family of enzymes provided the molecular basis for peroxide removal in these organisms. In this report the functional relevance of one of such enzymes, the mitochondrial 2-Cys peroxiredoxin (mTXNPx), was investigated along the Leishmania infantum life cycle. mTXNPx null mutants (mtxnpx(-)) produced by a gene replacement strategy, while indistinguishable from wild type promastigotes, were found unable to thrive in a murine model of infection. Unexpectedly, however, the avirulent phenotype of mtxnpx(-) was not due to lack of the peroxidase activity of mTXNPx as these behaved like controls when exposed to oxidants added exogenously or generated by macrophages during phagocytosis ex vivo. In line with this, mtxnpx(-) were also avirulent when inoculated into murine hosts unable to mount an effective oxidative phagocyte response (B6.p47(phox-/-) and B6.RAG2(-/-) IFN-γ(-/-) mice). Definitive conclusion that the peroxidase activity of mTXNPx is not required for parasite survival in mice was obtained by showing that a peroxidase-inactive version of this protein was competent in rescuing the non-infective phenotype of mtxnpx(-). A novel function is thus proposed for mTXNPx, that of a molecular chaperone, which may explain the impaired infectivity of the null mutants. This premise is based on the observation that the enzyme is able to suppress the thermal aggregation of citrate synthase in vitro. Also, mtxnpx(-) were more sensitive than controls to a temperature shift from 25°C to 37°C, a phenotype reminiscent of organisms lacking specific chaperone genes. Collectively, the findings reported here change the paradigm which regards all trypanosomatid 2-Cys peroxiredoxins as peroxide-eliminating devices. Moreover, they demonstrate, for the first time, that these 2-Cys peroxiredoxins can be determinant for pathogenicity independently of their peroxidase activity. |
| 5. | Proteomics. 2011 Nov;11(22). doi: 10.1002/pmic.201190123.In this issue.[No authors listed]AbstractMATCHING CUPS: Vesicles, as a means of transport and storage of information, have been around longer than humankind. In fact, it seems they have been used as a means of communication as long as eukaryotic cells have felt the need to gossip. They have used general external vesicle systems containing secreted metabolites (cytokines, hormones, and neurotransmitters), systems specifically related to the payload of external vesicles and methods dependent on the mechanism of vesicle formation (budding off, shedding from excetome) to convey information. Koppen et al. looked at the swirling mass of various sized vesicles surrounding Drosophila and asked "Where did these come from?" Not only were the microvesicles found in eukaryotes, but also in Drosophila, nematodes, pathogenic yeast and Leishmania parasites. Cell lines shedding vesicles included Hedgehog, Wnt and Wingless. Sizes range from 40 nm to 1 μm and generally have a common, cup-like structure. pp. 4397-4410 MOLES, WARTS, NEVI, UGLY BROWN SPOTS, MELANOMAS, MYCOSES, DERMATOPHYTES,...IN A WORD: UGLYS: Most of the uglys of the human race seem to be suffered by the adolescents, regardless of their natural skin color. Most of the human superficial mycoses are caused by a variety of dermatophytes, fungi that live on keratin. Many have been sequenced at the genome level (Microsporum canis, Arthroderma benhamiae). These fungi secrete virulence factors that are neutral or acidic proteases and peptidases including subtilisins, leucine amino peptidases, dipeptidyl-peptidases,and metallocarboxypeptidases. A particularly interesting feature of all of these fungi is that as they grow, they release metabolites that improve the pH of the growth medium and thus the rate of growth. When 2-D PAGE/shotgun LC was used to determine approximate numbers of active peptides, M. canis yielded 196 different hydrolases, including lipases, glucosidases, phosphatases, plus miscellaneous other enzymes (Background image obtained from CDC Public Health Image Library). pp. 4422-4433 TOO LATE FOR NEW TRICKS: Even software wears out in time - some of you may remember the millennium panic, when the turn of the calendar from 1999 to 2000 was going to knock the planes out of the air! Now we face the aging of proteomic and genomic analysis packages - our comfortable old shoes that cannot handle the load anymore. As of September 2011, the International Protein Index (IPI) will no longer be supported. Released in 2001, it mediated the differences between specific pairs of genomes - limited to seven specifically chosen models because of the cost of sequencing at that time. Currently there are more genomes sequenced and mutual aid agreements between analysis packages than you can shake a stick at. The replacement for IPI is UniProtKB complete Proteome set, comprising two databases, one manually curated (Swiss-Prot) and one automatically curated (TrEMBL). Griss et al. cover a number of issues surrounding the recommended substitutions (Image provided courtesy of UniProt Consortium). pp. 4434-4438. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
| 6. | Immunology. 2011 Oct 10. doi: 10.1111/j.1365-2567.2011.03519.x. [Epub ahead of print]CD40 and Tnf-Alpha Cooperate to Upregulate Nos2 Expression in Macrophages.Portillo JA, Feliciano LM, Okenka G, Heinzel F, Cecilia Subauste M, Subauste CS.SourceDivision of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106 Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106 Center for Global Health and Disease, Case Western Reserve University School of Medicine, Cleveland, OH 44106 Veterans Administration Medical Center, Research Service 151, Cleveland, OH 44106 Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106 Department of Ophthalmology and Visual Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106. AbstractRegulation of NOS2 expression is important given the role of this enzyme in inflammation, control of infections and immune regulation. In contrast to TNF-α alone or CD40 stimulation alone, simultaneous stimulation of mouse macrophages through CD40 ligation and TNF-α led to upregulation of NOS2 and nitric oxide production. This response was of functional relevance since CD40/TNF-α-stimulated macrophages acquired nitric oxide-dependent anti-Leishmania major activity. CD40 plus TNF-α upregulated NOS2 independently of IFN-γ, IFN-α/β and IL-1. TRAF6, an adapter protein downstream of CD40, appears to be required for NOS2 upregulation since a CD40-TRAF6 blocking peptide inhibited upregulation of NOS2 in CD40/TNF-α-stimulated macrophages. C/EBPβ, a transcription factor activated by TNF-α but not CD40, was required for NOS2 upregulation since this enzyme was not upregulated when C/EBPβ(-/-) macrophages received CD40 plus TNF-α stimulation. These results indicate that CD40 and TNF-α cooperate to upregulate NOS2, probably via the effect of TRAF6 and C/EBPβ. Journal compilation © 2011 Blackwell Publishing Ltd. |
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