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Abstract
Levels of intracellular ROS (reactive oxygen species) were significantly increased in hemocytes collected from WSSV-infected shrimp within the first 30–120 min after infection. Measurement of the NADPH/NADP+ and GSH/GSSG ratios revealed that after a significant imbalance toward the oxidized forms at 2 hpi, redox equilibrium was subsequently restored. Meanwhile, high levels of lactic acid production, elevated NADH/NAD+ ratios, and metabolic changes in the glycolysis pathway show that the Warburg effect was triggered by the virus. The timing of these changes suggests that WSSV uses this metabolic shift into aerobic glycolysis to counteract the high levels of ROS produced in response to viral infection. We further show that if the Warburg effect is inhibited by chemical inhibition of the PI3K-Akt-mTOR signaling pathway, or if the pentose phosphate pathway is chemically inhibited, then in both cases, the production of intracellular ROS is sustained. We conclude that WSSV uses the PI3K-Akt-mTOR-regulated Warburg effect to restore host redox balance and to counter the ROS produced by the host in response to WSSV infection. We also found that pyruvate kinase activity was inhibited by WSSV. This inhibition is likely to increase the availability of the raw materials essential for WSSV gene expression and replication.
Highlights
The production of reactive oxygen species (ROS) is an important cellular response that provides an infected shrimp with immediate protection
The results showed that white spot syndrome virus (WSSV) infection transiently induced high levels of ROS production at the initial stage of infection from 0.5 hpi to 2 hpi (Fig. 1)
The return to control levels at 1 hpi may reflect actual changes in production of ROS in the infected cell because while the DCF signal in Fig. 1 monitors the accumulated level of ROS, the flow cytometry used in Fig. 2 provides a better reflection of the ongoing dynamic regulation of the infected cells’ redox balance Fig. 2 implies that changes in the state of the cells might lead to a temporary pause in ROS production at around 1 hpi
Summary
The production of ROS is an important cellular response that provides an infected shrimp with immediate protection. The metabolic changes in these cells indicate that some glucose is diverted into lactic acid production instead of being catabolized by the tricarboxylic acid (TCA) cycle This re-routing is a defining characteristic of the Warburg effect. We used an in vivo shrimp metabolomics platform to monitor the characteristic changes induced by the Warburg effect in shrimp after WSSV infection These changes include the accumulation of lactic acid and the elevated glucose metabolism activity that occurs during the virus genome replication cycle. In vivo chemical inhibition of the PI3K-Akt-mTOR pathway and the pentose phosphate pathway was used to further elucidate how the WSSV-induced Warburg effect acts to neutralize the oxidative stress caused by the increase in ROS production
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