Distinct mechanisms of ER stress-mediated autophagy induction by high- and low-virulence pseudorabies virus strains.

Abstract

Pseudorabies virus (PRV) is one of the most significant pathogens threatening the swine industry, and its infection has caused substantial economic losses to pig farming worldwide. This study utilized two PRV strains isolated by our laboratory: the GXLB-2015 strain, a natural recombinant between a PRV variant strain and the Bartha-K61 vaccine strain, which exhibits stronger virulence, and the GXGG-2016 strain, a classical genotype II PRV strain with a natural 69-amino acid deletion in its TK gene, which demonstrates weak virulence and is non-pathogenic in mice. Focusing on endoplasmic reticulum stress (ERS) and cellular autophagy, this research explored the molecular mechanisms underlying the significant difference in virulence between these two PRV strains. The results revealed that infection with both strains induced noticeable ERS and autophagy, both of which inhibited viral replication. Further investigation showed that upon ERS induction, the GXLB-2015 strain mediated autophagy by activating both the PERK-eIF2α-ATF4-CHOP and IRE1-XBP1 pathways; inhibiting these pathways suppressed viral replication. In contrast, the GXGG-2016 strain infection mediated autophagy primarily through activating only the IRE1-XBP1 pathway, and inhibiting this pathway had no significant impact on viral replication. These findings indicate that while PRV infection can induce cellular autophagy by activating ERS, the specific unfolded protein response (UPR) pathways involved differ significantly between strains of varying virulence. This study provides a foundation for understanding the pathogenesis of different PRV strains and developing novel antiviral drugs.