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      An Invertebrate Warburg Effect: A Shrimp Virus Achieves Successful Replication by Altering the Host Metabolome via the PI3K-Akt-mTOR Pathway

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          In this study, we used a systems biology approach to investigate changes in the proteome and metabolome of shrimp hemocytes infected by the invertebrate virus WSSV (white spot syndrome virus) at the viral genome replication stage (12 hpi) and the late stage (24 hpi). At 12 hpi, but not at 24 hpi, there was significant up-regulation of the markers of several metabolic pathways associated with the vertebrate Warburg effect (or aerobic glycolysis), including glycolysis, the pentose phosphate pathway, nucleotide biosynthesis, glutaminolysis and amino acid biosynthesis. We show that the PI3K-Akt-mTOR pathway was of central importance in triggering this WSSV-induced Warburg effect. Although dsRNA silencing of the mTORC1 activator Rheb had only a relatively minor impact on WSSV replication, in vivo chemical inhibition of Akt, mTORC1 and mTORC2 suppressed the WSSV-induced Warburg effect and reduced both WSSV gene expression and viral genome replication. When the Warburg effect was suppressed by pretreatment with the mTOR inhibitor Torin 1, even the subsequent up-regulation of the TCA cycle was insufficient to satisfy the virus's requirements for energy and macromolecular precursors. The WSSV-induced Warburg effect therefore appears to be essential for successful viral replication.

          Author Summary

          The Warburg effect (or aerobic glycolysis) is a metabolic shift that was first found in cancer cells, but has also recently been discovered in vertebrate cells infected by viruses. The Warburg effect facilitates the production of more energy and building blocks to meet the enormous biosynthetic requirements of cancerous and virus-infected cells. To date, all of our knowledge of the Warburg effect comes from vertebrate cell systems and our previous paper was the first to suggest that the Warburg effect may also occur in invertebrates. Here, we use a state-of-the-art systems biology approach to show the global metabolomic and proteomic changes that are triggered in shrimp hemocytes by a shrimp virus, white spot syndrome virus (WSSV). We characterize several critical metabolic properties of the invertebrate Warburg effect and show that they are similar to the vertebrate Warburg effect. WSSV triggers aerobic glycolysis via the PI3K-Akt-mTOR pathway, and during the WSSV genome replication stages, we show that the Warburg effect is essential for the virus, because even when the TCA cycle is boosted in mTOR-inactivated shrimp, this fails to provide enough energy and materials for successful viral replication. Our study provides new insights into the rerouting of the host metabolome that is triggered by an invertebrate virus.

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          Most cited references 43

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          Understanding the Warburg effect: the metabolic requirements of cell proliferation.

          In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Aerobic glycolysis is an inefficient way to generate adenosine 5'-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.
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            On the origin of cancer cells.

             O WARBURG (1956)
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              Upstream and downstream of mTOR.

              The evolutionarily conserved checkpoint protein kinase, TOR (target of rapamycin), has emerged as a major effector of cell growth and proliferation via the regulation of protein synthesis. Work in the last decade clearly demonstrates that TOR controls protein synthesis through a stunning number of downstream targets. Some of the targets are phosphorylated directly by TOR, but many are phosphorylated indirectly. In this review, we summarize some recent developments in this fast-evolving field. We describe both the upstream components of the signaling pathway(s) that activates mammalian TOR (mTOR) and the downstream targets that affect protein synthesis. We also summarize the roles of mTOR in the control of cell growth and proliferation, as well as its relevance to cancer and synaptic plasticity.

                Author and article information

                Role: Editor
                PLoS Pathog
                PLoS Pathog
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                June 2014
                12 June 2014
                : 10
                : 6
                [1 ]Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan
                [2 ]Institute of Zoology, College of Life Science, National Taiwan University, Taipei, Taiwan
                [3 ]Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan
                [4 ]Center for Systems Biology, National Taiwan University, Taipei, Taiwan
                [5 ]Core Facilities for Protein Structural Analysis, Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
                [6 ]Academia Sinica Common Mass Spectrometry Facilities at Institute of Biological Chemistry, Taipei, Taiwan
                [7 ]Department of Life Science, College of Life Science, National Taiwan University, Taipei, Taiwan
                [8 ]Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan
                University of Washington, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: HCW. Performed the experiments: MAS YTH ITC DYL YCH CYL YAC SuYL ShYL SWH THN. Analyzed the data: MAS YTH HTY KHK GDC CFL HCW. Contributed reagents/materials/analysis tools: KHK GDC CFL. Wrote the paper: MAS HCW.


                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.

                Pages: 15
                This investigation was supported financially by the National Science Council (NSC 101-2321-B-006 -018 and NSC 102-2321-B-006 -008). The proteomic MS data were acquired at the former NRPGM Core Facilities for Proteomics and Glycomics (NSC 99-3112-B-001-025), at the Core Facilities for Protein Structural Analysis at Academia Sinica (NSC100-2325-B-001-029, NSC101-2319-B-001-003). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Biology and Life Sciences
                Shrimp Farming
                Systems Biology
                Veterinary Science
                Veterinary Diseases
                Veterinary Virology
                Veterinary Pathology

                Infectious disease & Microbiology


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