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      The Echinococcus granulosus Antigen B Gene Family Comprises at Least 10 Unique Genes in Five Subclasses Which Are Differentially Expressed

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          Abstract

          Background

          Antigen B (EgAgB) is a major protein produced by the metacestode cyst of Echinococcus granulosus, the causative agent of cystic hydatid disease. This protein has been shown to play an important role in modulating host immune responses, although its precise biological function still remains unknown. It is generally accepted that EgAgB is comprised of a gene family of five subfamilies which are highly polymorphic, but the actual number of genes present is unknown.

          Methodology/Principal Findings

          Based on published sequences for the family, we designed specific primers for each subfamily and used PCR to amplify them from genomic DNA isolated from individual mature adult worms (MAW) taken from an experimentally infected dog in China and individual larval protoscoleces (PSC) excised from a single hydatid cyst taken from an Australian kangaroo. We then used real-time PCR to measure expression of each of the genes comprising the five EgAgB subfamilies in all life-cycle stages including the oncosphere (ONC).

          Conclusions/Significance

          Based on sequence alignment analysis, we found that the EgAgB gene family comprises at least ten unique genes. Each of the genes was identical in both larval and adult E. granulosus isolates collected from two geographical areas (different continents). DNA alignment comparisons with EgAgB sequences deposited in GenBank databases showed that each gene in the gene family is highly conserved within E. granulosus, which contradicts previous studies claiming significant variation and polymorphism in EgAgB. Quantitative PCR analysis revealed that the genes were differentially expressed in different life-cycle stages of E. granulosus with EgAgB3 expressed predominantly in all stages. These findings are fundamental for determining the expression and the biological function of antigen B.

          Author Summary

          Antigen B (EgAgB) is a major protein produced by the metacestode cyst of Echinococcus granulosus and plays an important role in modulating host immune responses, although its precise biological function still remains unknown. Previous studies suggested the EgAgB gene family is variable between isolates and genotypic strains of E. granulosus. We designed specific primers to amplify and determine the number and variation of the genes using genomic DNA from individual worms. Based on sequence alignment analysis, we found that the gene family comprises ten unique genes. Each of the genes was identical in both larval and adult E. granulosus and in isolates collected from the two distinct geographical areas. We showed that the genes were differentially expressed in different stages of E. granulosus with one gene, EgAgB3/1, expressed predominantly in all stages. This is the first study to report such a large number of unique and conserved genes in the EgAgB gene family and their differential expression in different life cycle stages of E. granulosus. These findings are fundamental for determining the expression and regulation of this gene family in E. granulosus and the biological function of antigen B.

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          Most cited references 34

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          Concepts in immunology and diagnosis of hydatid disease.

          Echinococcosis is a cosmopolitan zoonosis caused by adult or larval stages of cestodes belonging to the genus Echinococcus (family Taeniidae). The two major species of medical and public health importance are Echinococcus granulosus and E. multilocularis, which cause cystic echinococcosis (CE) and alveolar echinococcosis (AE), respectively. Both CE and AE are both serious diseases, the latter especially so, with a high fatality rate and poor prognosis if managed inappropriately. This review discusses new concepts and approaches in the immunology and diagnosis of CE, but comparative reference has also been made to AE infection and to earlier pivotal studies of both diseases. The review considers immunity to infection in the intermediate and definitive hosts, innate resistance, evasion of the immune system, and vaccination of intermediate and definitive hosts, and it particularly emphasizes procedures for diagnosis of CE and AE, including the value of immunodiagnostic approaches. There is also discussion of the new advances in recombinant and related DNA technologies, especially application of PCR, that are providing powerful tools in the fields of vaccinology and molecular diagnosis of echinococcosis.
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            Modulation of human immune response by Echinococcus granulosus antigen B and its possible role in evading host defenses.

            By directly suppressing the function of certain immune cell subsets and by stimulating other cell populations related to immunopathology, parasite-derived substances play an important role in the chronic establishment of parasitic disease. Our objective was twofold: (i) to investigate further the role of Echinococcus granulosus antigen B (AgB) in the human early inflammatory response by determining its effect on polymorphonuclear cell (PMN) random migration, chemotaxis, and oxidative metabolism and (ii) to determine its action in acquired immunity by evaluating AgB and sheep hydatid fluid (SHF)-driven Th1 (gamma interferon [IFN-gamma] and interleukin 12 [IL-12]) and Th2 (IL-4 and IL-13) cytokine production by peripheral blood mononuclear cells (PBMC) from 40 patients who had cured or stable or progressive cystic echinococcosis. AgB significantly inhibited PMN recruitment but left their random migration and oxidative metabolism unchanged. Patients' PBMC stimulated with AgB produced IL-4 and IL-13 but did not produce IL-12. They also produced significantly lower IFN-gamma concentrations than did PBMC stimulated with SHF (P = 10(-5)). AgB skewed the Th1/Th2 cytokine ratios towards a preferentially immunopathology-associated Th2 polarization, predominantly in patients with progressive disease. AgB-stimulated patients' PBMC also proliferated less than SHF-stimulated PBMC (P = 9 x 10(-3)). In vitro Th2 cytokine production was reflected in vivo by elevated specific immunoglobulin E (IgE) and IgG4 antibodies binding to AgB. These findings confirm that AgB plays a role in the escape from early immunity by inhibiting PMN chemotaxis. They also add new information on the host-parasite relationship, suggesting that AgB exploits the activation of T helper cells by eliciting a nonprotective Th2 cell response.
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              Molecular cross-talk in host-parasite relationships: the intriguing immunomodulatory role of Echinococcus antigen B in cystic echinococcosis.

              Cystic echinococcosis (CE), a zoonosis caused by the development of Echinococcus granulosus tapeworm larvae in the internal organs of ungulates and humans, continues to pose a major public health burden in underdeveloped and industrialised areas worldwide. Research designed to improve parasitic disease control and find out more about parasite biology has already identified a number of E. granulosus antigenic molecules. The major E. granulosus immunomodulant antigen isolated from hydatid fluid is antigen B, a 120 kDa polymeric lipoprotein consisting of various 8 kDa subunits. By inhibiting elastase activity and neutrophil chemotaxis and eliciting a non-protective Th2 cell response, antigen B helps the parasite evade the human response. In this review, we briefly discuss current information on the molecular characteristics and immunomodulatory properties of E. granulosus antigen B. Besides focusing on findings that provide intriguing insights into the complex interplay between host and parasite, we suggest how this information could extend the current therapeutic options in inflammatory diseases.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                1935-2727
                1935-2735
                August 2010
                10 August 2010
                : 4
                : 8
                Affiliations
                [1 ]Molecular Parasitology Laboratory, Infectious Diseases Division, Queensland Institute of Medical Research, Brisbane, Queensland, Australia
                [2 ]Xinjiang Veterinary Research Institute, Xinjiang Academy of Animal Science, Urumqi, Xinjiang, China
                [3 ]School of Veterinary Science, University of Queensland, Brisbane, Queensland, Australia
                [4 ]School of Marine and Tropical Biology, James Cook University, Townsville, Queensland, Australia
                Rosetta Genomics, Israel
                Author notes

                Conceived and designed the experiments: WZ JL MKJ DPM. Performed the experiments: WZ JL. Analyzed the data: WZ JL MKJ DB DPM. Contributed reagents/materials/analysis tools: WZ JL MKJ ZZ LZ DPM. Wrote the paper: WZ DPM.

                Article
                09-PNTD-RA-0770R2
                10.1371/journal.pntd.0000784
                2919375
                20706625
                Zhang 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.
                Page count
                Pages: 11
                Categories
                Research Article
                Molecular Biology

                Infectious disease & Microbiology

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