D-glucose uptake inhibits bovine alphaherpesvirus 1 post-binding cell process entry via inhibition of PLC-γ1 signaling in a glucose transporter 1-independent manner

Bovine alphaherpesvirus 1 (BoAHV-1) is one of the most important viral pathogens responsible for severe economic losses in the cattle industry worldwide. We have previously shown that both phospholipase C gamma1 (PLC-γ1) and β-catenin signaling pathways play crucial roles in BoAHV-1 productive infection. In this study, we demonstrated that BoAHV-1 productive infection in bovine kidney (MDBK) cells and in bovine trigeminal ganglia neurons led to alteration of the protein expression and/or its subcellular localization glucose transporter 1 (GLUT1). In turn, GLUT1 signaling appeared to promote virus productive infection, partially by activating β-catenin-dependent transcriptional activity, as determined using GLUT1-specific small interfering RNAs or the GLUT1-specific inhibitor, BAY-876. Interestingly, D-glucose inhibited the virus post-bind ing cell entry process, partially through blocking PLC-γ1 signaling. Although GLUT1 is a key glucose transporter, the inhibitory effects of D-glucose on viral entry were independent of GLUT1. Moreover, we showed that D-glucose and the PLC-γ1-specific inhibitor U73122 synergistically inhibited virus cell entry. Collectively, for the first time, we revealed that D-glucose and its potential transporter GLUT1 had opposite effects on BoAHV-1 productive infection (inhibition vs promotion) via manipulation of different cell signaling pathways (PLC-γ1 vs β-catenin). These findings provide novel insights into the mechanisms underlying BoAHV-1 infection involving GLUT1 and glucose and highlight potential therapeutic targets for the development of antiviral strategies.