Date Published: June 12, 2014
Publisher: Public Library of Science
Author(s): Mei-An Su, Yun-Tzu Huang, I-Tung Chen, Der-Yen Lee, Yun-Chieh Hsieh, Chun-Yuan Li, Tze Hann Ng, Suh-Yuen Liang, Shu-Yu Lin, Shiao-Wei Huang, Yi-An Chiang, Hon-Tsen Yu, Kay-Hooi Khoo, Geen-Dong Chang, Chu-Fang Lo, Han-Ching Wang, Michael Lagunoff.
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.
The Warburg effect, which was first described by Warburg in the 1930s, is a metabolic rerouting used by tumor cells and cancer cells to support their high energy requirements and high rates of macromolecular synthesis , . In cancer cells, the main hallmark of the Warburg effect is aerobic glycolysis, in which glucose consumption and lactate production are both increased even in the presence of oxygen . Several other metabolic pathways are also enhanced, including the pentose phosphate pathway (PPP), amino acid metabolism and lipid homeostasis. The Warburg effect can also be induced in vitro by some vertebrate viruses, including human papillomavirus (HPV) ; human cytomegalovirus (HCMV) , , Kaposi’s sarcoma herpesvirus (KSHV)  and hepatitis C virus (HCV) , and recently we reported an in vivo Warburg-like effect that was induced in shrimp hemocytes by the white spot syndrome virus (WSSV; genus Whispovirus, family Nimaviridae) .
Although only a limited number of vertebrate viruses (HCMV, HCV, Dengue virus, influenza virus, HSV and KSHV) have been studied using a systems biology approach , , , –, in the present study, several metabolic pathways that are often altered in cancer/tumor cells and virus-infected vertebrate cells also seemed to be similarly affected by WSSV infection (Fig. 1 and Tables S1, S2). These altered metabolic pathways included glycolysis, the PPP, the biosynthesis of nucleic and amino acids, and the TCA cycle.