Glucose- and glutamine-driven de novo nucleotide synthesis facilitates WSSV replication in shrimp
Journal
Cell Communication and Signaling
Journal Volume
23
Journal Issue
1
ISSN
1478-811X
Date Issued
2025-04-22
Author(s)
Cong-Yan Chen
Chih-Ling Chen
Yen Siong Ng
Der-Yen Lee
Ramya Kumar
Han-Ching Wang
Abstract
Background
Viruses rely on host metabolism to complete their replication cycle. White spot syndrome virus (WSSV), a major pathogen in shrimp aquaculture, hijacks host metabolic pathways to fulfill its biosynthetic and energetic needs. Previous studies have demonstrated that WSSV promotes aerobic glycolysis (Warburg effect) and glutaminolysis during its replication stage (12 hpi). Therefore, glucose and glutamine serve as crucial metabolites for viral replication. Additionally, de novo nucleotide synthesis, including the pentose phosphate pathway and purine/pyrimidine synthesis, is significantly activated during WSSV infection. However, the precise association between WSSV and host glucose and glutamine metabolism in driving de novo nucleotide synthesis remains unclear. This study aimed to investigate the involvement of glucose and glutamine in nucleotide metabolism during WSSV replication and to elucidate how WSSV reprograms these pathways to facilitate its pathogenesis.
Methods
To assess changes in metabolic flux during WSSV replication, LC-ESI-MS-based isotopically labeled glucose ([U-13C] glucose) and glutamine ([A-15N] glutamine) were used as metabolic tracers in in vivo experiments with white shrimp (Litopenaeus vannamei). The in vivo experiments were also conducted to measure the expression and enzymatic activity of genes involved in nucleotide metabolism. Additionally, in vivo dsRNA-mediated gene silencing was employed to evaluate the roles of these genes in WSSV replication. Pharmacological inhibitors targeting the Ras-PI3K-Akt-mTOR pathway were also applied to investigate its regulatory role in WSSV-induced nucleotide metabolic reprogramming.
Results
The metabolite tracking analysis confirmed that de novo nucleotide synthesis was significantly activated at the WSSV replication stage (12 hpi). Glucose metabolism is preferentially reprogrammed to support purine synthesis, while glutamine uptake is significantly increased and contributes to both purine and pyrimidine synthesis. Consistently, gene expression and enzymatic activity analyses, along with gene silencing experiments, indicated the critical role of de novo nucleotide synthesis in supporting viral replication. However, while the inhibition of the Ras-PI3K-Akt-mTOR pathway suggested its involvement in regulating nucleotide metabolism, no consistent effect on WSSV replication was observed, suggesting the presence of alternative regulatory mechanisms.
Conclusion
This study demonstrates that WSSV infection induces specific metabolic reprogramming of glucose and glutamine utilization to facilitate de novo nucleotide synthesis in shrimp. These metabolic changes provide the necessary precursors for nucleotide synthesis, supporting WSSV replication and pathogenesis. The findings offer novel insights into the metabolic strategies employed by WSSV and suggest potential targets for controlling WSSV outbreaks in shrimp aquaculture.
Subjects
de novo nucleotide metabolism
in vivo stable-isotope tracing metabolomics
Pentose phosphate pathway
Warburg effect
White shrimp
White spot syndrome virus
Publisher
Springer Science and Business Media LLC
Description
Article number: 191
Type
journal article