Phospholipid codes at virus-host membrane interfaces: mechanisms and therapeutic opportunities in animal viral diseases

Abstract

Animal viruses depend on host membranes at every stage of infection, yet membrane lipid states are often treated as background rather than as causal determinants of virus-host interactions. This Review develops a phospholipid-code framework in which headgroup identity, acyl-chain chemistry, leaflet topology, and lipid flux define infection-stage-specific membrane states. Evidence from Newcastle disease virus, infectious bronchitis virus, avian influenza virus, porcine reproductive and respiratory syndrome virus, African swine fever virus, Senecavirus A, Japanese encephalitis virus, and porcine epidemic diarrhea virus shows that these states can control attachment, endosomal progression, growth of replication organelles, viral protein allostery, budding, virion infectivity, ferroptotic tissue injury, and delivery of vaccines or antivirals. Comparative evidence from human and plant virus systems is used only to identify transferable membrane mechanisms that require validation in animal-virus models and natural host species. The framework distinguishes viral lipid demand from host defense and tissue damage and explains why total-cell lipidomics or broad metabolic inhibitors rarely establish causality. We argue that the most promising interventions will target viral protein-lipid interfaces, virus-specific recruitment of lipid-transfer machinery, transient leaflet transitions, virion envelopes, or pathological lipid oxidation rather than globally suppressing essential lipid metabolism. Species-relevant primary cells, organoids, virion lipidomics, topology-resolved assays, acute perturbation, rescue experiments, and animal challenge models will be required to translate causal phospholipid biology into safe and practical antiviral strategies for livestock and poultry health.