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      Host insulin stimulates Echinococcus multilocularis insulin signalling pathways and larval development

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          Abstract

          Background

          The metacestode of the tapeworm Echinococcus multilocularis is the causative agent of alveolar echinococcosis, a lethal zoonosis. Infections are initiated through establishment of parasite larvae within the intermediate host’s liver, where high concentrations of insulin are present, followed by tumour-like growth of the metacestode in host organs. The molecular mechanisms determining the organ tropism of E. multilocularis or the influences of host hormones on parasite proliferation are poorly understood.

          Results

          Using in vitro cultivation systems for parasite larvae we show that physiological concentrations (10 nM) of human insulin significantly stimulate the formation of metacestode larvae from parasite stem cells and promote asexual growth of the metacestode. Addition of human insulin to parasite larvae led to increased glucose uptake and enhanced phosphorylation of Echinococcus insulin signalling components, including an insulin receptor-like kinase, EmIR1, for which we demonstrate predominant expression in the parasite’s glycogen storage cells. We also characterized a second insulin receptor family member, EmIR2, and demonstrated interaction of its ligand binding domain with human insulin in the yeast two-hybrid system. Addition of an insulin receptor inhibitor resulted in metacestode killing, prevented metacestode development from parasite stem cells, and impaired the activation of insulin signalling pathways through host insulin.

          Conclusions

          Our data indicate that host insulin acts as a stimulant for parasite development within the host liver and that E. multilocularis senses the host hormone through an evolutionarily conserved insulin signalling pathway. Hormonal host-parasite cross-communication, facilitated by the relatively close phylogenetic relationship between E. multilocularis and its mammalian hosts, thus appears to be important in the pathology of alveolar echinococcosis. This contributes to a closer understanding of organ tropism and parasite persistence in larval cestode infections. Furthermore, our data show that Echinococcus insulin signalling pathways are promising targets for the development of novel drugs.

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          Most cited references46

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          Signalling by insulin and IGF receptors: supporting acts and new players.

          The signalling pathways utilised by insulin receptor (IR) and IGF receptor to transduce their diverse effects on cellular metabolism, growth and survival are well established in broad outline, but many details remain to be elucidated. Tyrosine phosphorylation of IR substrates and Shc initiates signalling via canonical phosphoinositide 3-kinase/Akt and Ras/MAP kinase pathways, which together mediate many of the actions of insulin and IGFs. However, a variety of additional substrates and scaffolds have been described that may play roles in modulating the canonical pathways or in specific biological responses. This review will focus on recent studies that have extended our understanding of insulin/IGF signalling pathways, and the elements that may contribute to specificity.
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            Molecular mechanisms of metabolic regulation by insulin in Drosophila.

            The insulin signalling pathway is highly conserved from mammals to Drosophila. Insulin signalling in the fly, as in mammals, regulates a number of physiological functions, including carbohydrate and lipid metabolism, tissue growth and longevity. In the present review, I discuss the molecular mechanisms by which insulin signalling regulates metabolism in Drosophila, comparing and contrasting with the mammalian system. I discuss both the intracellular signalling network, as well as the communication between organs in the fly.
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              Clinical features and treatment of alveolar echinococcosis.

              Peter Kern (2010)
              Human alveolar echinococcosis is caused by the larval stage of Echinococcus multilocularis, occurring in at least 42 countries of the northern hemisphere. Recent studies in Europe and Asia have shown that the endemic area of E. multilocularis is larger than previously known and the parasite has regionally expanded from rural to urban areas. Diagnosis of alveolar echinococcosis is supported by results from imaging studies, histopathology and/or nucleic acid detection, and serology. The present review summarizes current understanding of clinical features, knowledge on appropriate treatment, and discusses ways to improve standards of care. High prevalences of this deadly disease have been discovered in surveys in parts of China. Clinical manifestations, diagnostic tools and the burden of disease were described, and are based on high case numbers. In Europe, excellent tools have been introduced, which improve disease management. Long-term observations in Switzerland provide an optimistic view, as the infection can be well controlled, if patients are cared for in specialized centres. An expert consensus summarizes the current recommendation for diagnosis and treatment of alveolar echinococcosis by the Informal Working Group on Echinococcosis of the WHO. Diagnosis and treatment of alveolar echinococcosis remains a challenge for clinicians. The updated WHO-recommendations aim to support decisions on diagnosis and treatment of alveolar echinococcosis. Anti-infective therapy is the backbone of treatment; surgery should be restricted to patients at an early stage of the disease. For the majority of cases continuous chemoprophylaxis with benzimidazoles is cost-effective and leads to a good quality of life for patients with this chronic disease.
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                Author and article information

                Journal
                BMC Biol
                BMC Biol
                BMC Biology
                BioMed Central
                1741-7007
                2014
                27 January 2014
                : 12
                : 5
                Affiliations
                [1 ]University of Würzburg, Institute of Hygiene and Microbiology, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany
                [2 ]Department of Bioinformatics, University of Würzburg, Biocenter am Hubland, D-97074 Würzburg, Germany
                [3 ]Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Bern, Switzerland
                Article
                1741-7007-12-5
                10.1186/1741-7007-12-5
                3923246
                24468049
                09592950-59a6-474a-8c0e-2999f6991b51
                Copyright © 2014 Hemer et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 18 November 2013
                : 21 January 2014
                Categories
                Research Article

                Life sciences
                insulin,kinase inhibitor,tapeworm,receptor kinase,host-parasite interaction,echinococcus,cestode,echinococcosis

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