Newcastle disease virus acquires phosphatidylserine through the budding process to enhance infectivity

Newcastle disease, a highly contagious avian illness caused by the Newcastle disease virus (NDV), inflicts substantial economic losses upon the global poultry industry. While NDV is known to enter host cells via multiple pathways, critical aspects of its infection and pathogenic mechanisms, particularly the role of host lipids, remain incompletely understood. Here, we demonstrate that NDV infection strategically manipulates host phosphatidylserine (PS) metabolism to enhance its replication cycle. We found that the NDV hemagglutinin-neuraminidase (HN) protein triggers an elevation in intracellular Ca²⁺ levels, which in turn activates the host phospholipid scramblase TMEM16F. This activation leads to the externalization of PS to the outer leaflet of the plasma membrane. Consequently, NDV virions budding from these PS-rich membrane domains acquire a PS-enriched envelope. Mass spectrometry analysis confirmed high PS abundance on the viral surface. These PS-decorated progeny virions then engage host cell PS receptors, specifically the receptor tyrosine kinase TYRO3 and T-cell immunoglobulin and mucin domain-containing receptor 4 (TIM-4), to facilitate enhanced viral adsorption and entry. This process, known as “apoptotic mimicry,” represents a novel, parallel entry pathway for NDV. These findings provide new mechanistic insights into NDV-host interactions and identify the PS scrambling and recognition axis as a potential therapeutic target for developing novel anti-NDV strategies.