Infectious spleen and kidney necrosis virus promotes replication organelle formation and sphingolipid biosynthesis to facilitate viral replication.

Abstract

Infectious spleen and kidney necrosis virus (ISKNV) is a highly pathogenic iridovirus that causes severe economic losses in aquaculture. Viruses usually remodel host lipid metabolism to facilitate their replication. However, whether ISKNV modulates host lipid metabolism to support its infection remains unknown. In this study, using lipidomics analysis, we found that ISKNV infection induced widespread upregulation of host lipid profiles, including glycerophospholipids, glycerolipids, and sphingolipids. Transcriptional analysis revealed coordinated regulation of key metabolic enzymes, collectively favoring lipid accumulation. Notably, ISKNV infection increased the levels and proportions of unsaturated fatty acid-containing lipids from the early stage (24 hours post-infection, hpi), promoting the formation of membrane vesicles that act as replication organelles. Accordingly, transmission electron microscopy revealed abundant vesicles containing virions in infected cells at the late stage (72 hpi). Furthermore, lipidomics analysis demonstrated that ISKNV activated sphingolipid biosynthesis at 72 hpi, leading to ceramide accumulation. Pharmacological inhibition of serine palmitoyltransferase (Spt) or ceramide synthase (CerS) significantly suppressed viral replication, underscoring the functional importance of sphingolipid pathway. Collectively, these findings demonstrate that ISKNV hijacks host lipid metabolism through two mechanisms: 1) increasing of unsaturated fatty acid-containing lipids to facilitate the formation of viral replication organelles, and 2) activating sphingolipid biosynthesis to promote ceramide accumulation. This study provides a mechanistic basis for ISKNV pathogenesis and identifies host lipid metabolic pathways as potential therapeutic targets against this aquaculture pathogen.