Picornavirus infection enhances aspartate by the SLC38A8 transporter to promote viral replication

Author summaryViruses can utilize cells to synthesize many metabolites required for self-replication. However, the impact of foot-and-mouth disease virus (FMDV) infection on host cellular metabolism remains unknown. Here, we analyzed the metabolomic profiles in FMDV-infected PK-15 cells and pigs for the first time. FMDV infection significantly enhanced aspartate, and the solute carrier family 38 member 8 transporter was responsible for this effect. FMDV infection activated the mTOR/p70S6K1 signaling axis to promote viral replication. This study revealed how FMDV uses amino acids to promote viral replication, which is important for guiding the design of new preventive measures against FMDV targeting the altered metabolic pathways. Foot-and-mouth disease, a class of animal diseases, is caused by foot-and-mouth disease virus (FMDV). The metabolic changes during FMDV infection remain unclear. Here, PK-15 cells, serum, and tonsils infected with FMDV were analyzed by metabolomics. A total of 284 metabolites in cells were significantly changed after FMDV infection, and most of them belong to amino acids and nucleotides. Further studies showed that FMDV infection significantly enhanced aspartate in vitro and in vivo. The amino acid transporter solute carrier family 38 member 8 (SLC38A8) was responsible for FMDV-upregulated aspartate. Enterovirus 71 (EV71) and Seneca Valley virus (SVV) infection also enhanced aspartate by SLC38A8. Aspartate aminotransferase activity was also elevated in FMDV-, EV71-, and SVV-infected cells, which may lead to reversible transition between the TCA cycle and amino acids synthesis. Aspartate and SLC38A8 were essential for FMDV, EV71, and SVV replication in cells. In addition, aspartate and SLC38A8 also promoted FMDV and EV71 replication in mice. Detailed analysis indicated that FMDV infection promoted the transfer of mTOR to lysosome to enhance interaction between mTOR and Rheb, and activated PI3K/AKT/TSC2/Rheb/mTOR/p70S6K1 pathway to promote viral replication. The mTORC1 signaling pathway was responsible for FMDV-induced SLC38A8 protein expression. For the first time, our data identified metabolic changes during FMDV infection. These data identified a novel mechanism used by FMDV to upregulate aspartate to promote viral replication and will provide new perspectives for developing new preventive strategies.

Automated summary

This study analyzed the metabolic changes during foot-and-mouth disease virus (FMDV) infection and revealed the virus's ability to utilize amino acids to promote replication. The findings provide new insights for developing preventive strategies against FMDV.