Porcine epidemic diarrhea virus manipulates IMPDH-dependent nucleotide biosynthesis to facilitate replication.

Abstract

UNLABELLED: Porcine epidemic diarrhea virus (PEDV) causes acute intestinal disease in pigs and remains a major threat to the global swine industry due to its high morbidity and mortality in neonatal piglets. To investigate host metabolic alterations upon PEDV infection, we performed untargeted metabolomic profiling in LLC-PK1 and Vero E6 cells. Pathway enrichment analysis revealed significant changes in nucleotide metabolism, cofactor biosynthesis, amino acid biosynthesis, and purine metabolism. Notably, PEDV infection led to divergent regulation of purine metabolism in the two cell types-upregulation in Vero E6 cells and downregulation in LLC-PK1 cells at 18 h post-infection. We further identified inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in guanine nucleotide biosynthesis, as a critical host factor for PEDV replication. Both genetic knockdown of IMPDH2 and pharmacological inhibition using merimepodib (VX-497, MMPD) significantly reduced viral RNA levels and impaired replication. These treatments also suppressed host nucleotide biosynthetic activity. Together, our findings demonstrate that PEDV hijacks the IMPDH-dependent guanosine biosynthesis pathway to support its replication and identify IMPDH as a promising host-directed antiviral target against PEDV. IMPORTANCE: PEDV poses a major global threat to swine health. This study uncovers a key mechanism of pathogenesis: PEDV exploits host nucleotide metabolism, inducing significant reprogramming with emphasis on purine biosynthesis. Comparative infection of porcine (LLC-PK1) and primate (Vero E6) cells revealed cell-specific metabolic adaptations. Crucially, we identify inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme for guanosine biosynthesis, as an essential host dependency factor for PEDV replication. Inhibiting IMPDH genetically or pharmacologically significantly reduced viral titers, validating it as a critical vulnerability. These findings reveal a novel mechanism by which PEDV hijacks host metabolism and establishes IMPDH as a promising host-directed therapeutic target for combating this economically devastating virus.