Lactate facilitates largemouth bass virus replication by promoting cholesterol biosynthesis

Cellular metabolism has been hijacked by viruses for efficient replication due to their regulatory roles on both innate and adaptive immunity. Largemouth bass virus (LMBV), a member of Ranavirus, causes high mortality and severe economic losses in several fish species, seriously threatening the sustainable development of aquaculture industry. However, the roles of the metabolic events in LMBV replication remained largely uncertain. Here, our results showed that LMBV boosted aerobic glycolysis both in vitro and in vivo. Supplement with glucose significantly enhanced LMBV replication in vitro. Consistently, blocking glycolysis with 2DG or lactate biosynthesis with oxamate markedly decreased LMBV replication, as indicated by reduced viral gene expression, protein synthesis, and virus titers. Interestingly, exogenous lactate also significantly promoted LMBV replication. Mechanistically, lactate not only reduced interferon response triggered by poly(I:C), but also promoted cholesterol biosynthesis. Further analysis showed that lactate induced cholesterol biosynthesis might inhibit LMBV induced IRF3 phosphorylation, and reduce the expression levels of IFN-stimulated genes (e.g., IFN1, IFNγ, IRF3, IRF7, ISG20, MX). These findings suggest that lactate might facilitate LMBV replication by enhancing cholesterol biosynthesis and inhibiting host interferon response. Our results provided new insights into understanding the roles of metabolic reprogramming during iridovirus infection.