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The Sigma Class Glutathione Transferase from the Liver Fluke Fasciola hepatica

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      Abstract

      Background

      Liver fluke infection of livestock causes economic losses of over US$ 3 billion worldwide per annum. The disease is increasing in livestock worldwide and is a re-emerging human disease. There are currently no commercial vaccines, and only one drug with significant efficacy against adult worms and juveniles. A liver fluke vaccine is deemed essential as short-lived chemotherapy, which is prone to resistance, is an unsustainable option in both developed and developing countries. Protein superfamilies have provided a number of leading liver fluke vaccine candidates. A new form of glutathione transferase (GST) family, Sigma class GST, closely related to a leading Schistosome vaccine candidate (Sm28), has previously been revealed by proteomics in the liver fluke but not functionally characterised.

      Methodology/Principal Findings

      In this manuscript we show that a purified recombinant form of the F. hepatica Sigma class GST possesses prostaglandin synthase activity and influences activity of host immune cells. Immunocytochemistry and western blotting have shown the protein is present near the surface of the fluke and expressed in eggs and newly excysted juveniles, and present in the excretory/secretory fraction of adults. We have assessed the potential to use F. hepatica Sigma class GST as a vaccine in a goat-based vaccine trial. No significant reduction of worm burden was found but we show significant reduction in the pathology normally associated with liver fluke infection.

      Conclusions/Significance

      We have shown that F. hepatica Sigma class GST has likely multi-functional roles in the host-parasite interaction from general detoxification and bile acid sequestration to PGD synthase activity.

      Author Summary

      Combating neglected parasitic diseases is of paramount importance to improve the health of human populations and/or their domestic animals. Uncovering key roles in host-parasite interactions may support the vaccine potential portfolio of a parasite protein. Fasciola hepatica causes global disease in humans and their livestock but no commercial vaccines are available. Members of the Sigma class glutathione transferase (GST) family have long been highlighted as vaccine candidates towards parasitic flatworms. To this end, a Sigma class GST is currently undergoing phase II clinical trials to protect against infection from the schistosomes. In this study we characterise the protein from F. hepatica following four work pathways that 1) confirm its designation as a Sigma class GST using substrate profiling, 2) assess prostaglandin synthase activity and its effect on host immune cells, 3) localise the Sigma GST within adult fluke and between ontogenic stages and 4) measure its potential as a vaccine candidate. The work presented here shows F. hepatica Sigma class GST to have key host-parasite roles and we suggest, warrants further investigation for inclusion into vaccine formulations.

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      Most cited references 75

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      The neighbor-joining method: a new method for reconstructing phylogenetic trees.

       N Saitou,  M Nei (1987)
      A new method called the neighbor-joining method is proposed for reconstructing phylogenetic trees from evolutionary distance data. The principle of this method is to find pairs of operational taxonomic units (OTUs [= neighbors]) that minimize the total branch length at each stage of clustering of OTUs starting with a starlike tree. The branch lengths as well as the topology of a parsimonious tree can quickly be obtained by using this method. Using computer simulation, we studied the efficiency of this method in obtaining the correct unrooted tree in comparison with that of five other tree-making methods: the unweighted pair group method of analysis, Farris's method, Sattath and Tversky's method, Li's method, and Tateno et al.'s modified Farris method. The new, neighbor-joining method and Sattath and Tversky's method are shown to be generally better than the other methods.
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        CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice.

        The sensitivity of the commonly used progressive multiple sequence alignment method has been greatly improved for the alignment of divergent protein sequences. Firstly, individual weights are assigned to each sequence in a partial alignment in order to down-weight near-duplicate sequences and up-weight the most divergent ones. Secondly, amino acid substitution matrices are varied at different alignment stages according to the divergence of the sequences to be aligned. Thirdly, residue-specific gap penalties and locally reduced gap penalties in hydrophilic regions encourage new gaps in potential loop regions rather than regular secondary structure. Fourthly, positions in early alignments where gaps have been opened receive locally reduced gap penalties to encourage the opening up of new gaps at these positions. These modifications are incorporated into a new program, CLUSTAL W which is freely available.
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          The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools.

          CLUSTAL X is a new windows interface for the widely-used progressive multiple sequence alignment program CLUSTAL W. The new system is easy to use, providing an integrated system for performing multiple sequence and profile alignments and analysing the results. CLUSTAL X displays the sequence alignment in a window on the screen. A versatile sequence colouring scheme allows the user to highlight conserved features in the alignment. Pull-down menus provide all the options required for traditional multiple sequence and profile alignment. New features include: the ability to cut-and-paste sequences to change the order of the alignment, selection of a subset of the sequences to be realigned, and selection of a sub-range of the alignment to be realigned and inserted back into the original alignment. Alignment quality analysis can be performed and low-scoring segments or exceptional residues can be highlighted. Quality analysis and realignment of selected residue ranges provide the user with a powerful tool to improve and refine difficult alignments and to trap errors in input sequences. CLUSTAL X has been compiled on SUN Solaris, IRIX5.3 on Silicon Graphics, Digital UNIX on DECstations, Microsoft Windows (32 bit) for PCs, Linux ELF for x86 PCs, and Macintosh PowerMac.
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            Author and article information

            Affiliations
            [1 ]Institute of Biological, Environmental and Rural Sciences, Aberystwyth University, Aberystwyth, Wales, United Kingdom
            [2 ]Molecular and Biochemical Parasitology Group, Liverpool School of Tropical Medicine, Liverpool, England, United Kingdom
            [3 ]School of Biological Sciences, University of Liverpool, Liverpool, England, United Kingdom
            [4 ]Faculty of Science and Health, Dublin City University, Dublin, Ireland
            [5 ]Faculty of Veterinary Science, University of Liverpool, Liverpool, England, United Kingdom
            [6 ]School of Biological Sciences, Queen's University of Belfast, Belfast, Northern Ireland, United Kingdom
            [7 ]School of Veterinary Medicine, University of Córdoba, Córdoba, Spain
            University of Queensland, Australia
            Author notes

            Conceived and designed the experiments: EJL PMB. Performed the experiments: EJL SP RMM JVM MP DJD AK UH RZ LB. Analyzed the data: EJL ROM. Contributed reagents/materials/analysis tools: EH. Wrote the paper: EJL RMM JPA SMO PMB.

            Contributors
            Role: Editor
            Journal
            PLoS Negl Trop Dis
            PLoS Negl Trop Dis
            plos
            plosntds
            PLoS Neglected Tropical Diseases
            Public Library of Science (San Francisco, USA )
            1935-2727
            1935-2735
            May 2012
            29 May 2012
            : 6
            : 5
            3362645
            22666515
            PNTD-D-11-01206
            10.1371/journal.pntd.0001666
            (Editor)
            LaCourse et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Counts
            Pages: 14
            Categories
            Research Article
            Biology
            Biochemistry
            Cytochemistry
            Histochemistry
            Proteins
            Recombinant Proteins
            Microbiology
            Parasitology
            Medicine
            Clinical Immunology
            Immunity
            Vaccination
            Vaccine Development
            Veterinary Science
            Veterinary Diseases
            Veterinary Parasitology

            Infectious disease & Microbiology

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