Abstract

Newcastle disease virus (NDV), a significant avian pathogen and promising oncolytic agent, relies on host metabolic pathways for replication. However, the metabolic alterations induced by NDV, particularly the connections at the gene and protein levels, remain poorly characterized. This study employed integrated transcriptomic, proteomic, and non-targeted metabolomic analyses to delineate the global metabolic changes in NDV-infected A549 cells. We identified 8,101 differentially expressed genes (DEGs), 1,587 differentially expressed proteins (DEPs), and 257 differentially expressed metabolites (DEMs) associated with organelle function, innate immunity, and metabolism. Crucially, our multi-omics approach revealed that NDV significantly remodels glycerophospholipid metabolism. NDV depleted Lysophosphatidylcholine (LPC) and Lysophosphatidylethanolamine (LPE), as well as specific phosphatidylcholine (PC) and phosphatidylethanolamine (PE) species, while increasing phosphatidylserine (PS) at the late stage of infection. Strikingly, exogenous supplementation of unsaturated fatty acids, choline, phosphorylcholine, ethanolamine, phosphatidylethanolamine, and inositol markedly enhanced NDV replication. Concomitantly, NDV infection upregulated the transcriptional levels of key enzymes involved in glycerophospholipid biosynthesis. This study demonstrates for the first time that NDV actively reprograms host glycerophospholipid metabolism to facilitate viral replication. This study uncovers a novel mechanism of NDV-host interaction and provides crucial insights for oncolytic strategies targeting this metabolic vulnerability.