Multi-Omics Analyses Reveal Metabolic Alterations Regulated by Orf Virus in Primary Ovine Fetal Turbinate Cells

<i>Orf virus</i> (ORFV) is a member of the Parapoxvirus genus of the Poxviridae family causing contagious diseases in sheep, goats, and wild ungulates, with zoonotic potential in humans. Although many viruses, including poxviruses, are known to utilize the host cellular machinery to reproduce viral particles, the metabolic changes induced by ORFV remain unclear. In the present study, non-targeted metabolomics and proteomics were employed to investigate the impact of ORFV infection on the host cellular metabolism network. A total of 301 metabolites and 802 proteins were significantly altered during the early stages of ORFV infection, and most of them were involved in cellular lipid metabolism, amino acid metabolism, nucleotide metabolism, and glucose metabolism. We further determined the effect of the host's metabolic system on ORFV replication using the TCID₅₀ assay. Virus titers were significantly decreased in the absence of glucose or when treated with the de novo fatty acid synthesis inhibitor, indicating that glucose metabolism and de novo fatty acid synthesis pathway were required for ORFV replication. However, glutamine did not affect viral titers. Our findings provide insights into ORFV-host interactions, which are critical for developing new preventive or therapeutic strategies against ORFV by targeting altered metabolic pathways.