Abstract
Lipids metabolism plays a significant role in cellular responses to virus pathogens. However, the impact of lipids metabolism in CSFV infection is not yet confirmed. In the present study, for the fist time, we performed serum lipidomics analysis of piglets infected with CSFV based on ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS), and identified 167 differentially expressed lipid metabolites. Interestingly, free fatty acids (FFAs) accumulated significantly in these metabolites, accompanied by an increase in sphingolipids and a decrease in glycerolipids and glycerophospholipids, suggesting that CSFV infection markedly changed the serum lipid metabolism of piglets. FFAs are the principal constituents of many complex lipids and are essential substrates for energy metabolism. Based on this, we focused on whether FFAs play a prominent role in CSFV infection. We found that CSFV infection induced FFAs accumulation in vivo and in vitro, which is due to increased fatty acid biosynthesis. Meanwhile, we discovered that alteration of cellular FFAs accumulation by a mixture of FFAs or inhibitors of fatty acid biosynthesis affects progeny virus production in vitro. Furthermore, in the absence of glucose or glutamine, CSFV still has replication capacity, which is significantly reduced with the addition of fatty acid beta oxidation inhibitors, suggesting that the process of FFAs enter the mitochondria for beta oxidation to produce ATP is necessary for virus replication. Finally, we demonstrated CSFV induced FFAs accumulation results in impaired type I IFN signaling-mediated antiviral responses by down-regulating RIG-I-like receptors (RLRs) signaling molecules, which may represent a mechanism of CSFV replication. Taken together, these findings provide the first data on lipid metabolites during CSFV infection and reveal a new view that CSFV infection requires FFAs to enhance viral replication.
Highlights
Classical swine fever virus (CSFV) is a member of the Pestivirus genus within the Flaviviridae family that is the causative agent of classical swine fever (CSF) in pigs and its genome consists of a single-stranded positive-sense genomic RNA of about 12.5 kb (Becher et al, 2003)
A total of ten 2-month-old piglets were randomly divided into two groups, one challenged with 105 TCID50 of CSFV (Group S) and one inoculated with an equal volume of normal PK-15 cell-culture supernatant served as negative controls (Group C) (n = 5 each), and the rectal temperature and the blood viral load were daily detected after infection
We provided for the first time observations on the lipids changes in the serum of CSFV-infected piglets based on UHPLC-QTOF-MS, which might provide suitable targets for drug intervention and therapeutic vaccines
Summary
Classical swine fever virus (CSFV) is a member of the Pestivirus genus within the Flaviviridae family that is the causative agent of classical swine fever (CSF) in pigs and its genome consists of a single-stranded positive-sense genomic RNA of about 12.5 kb (Becher et al, 2003). CSF has a serious destructive effect on the immune and hematopoietic system, causing a series of clinical symptoms such as high fever, multiple hemorrhage, leukopenia, neurological dysfunction, abortion, and high mortality, which seriously endangers the healthy development of pig industry worldwide (Kleiboeker, 2002; Lohse et al, 2012). CSF is largely controlled through mass vaccination because of limited treatment options (König et al, 1995; Moormann et al, 2000). To develop new vaccines or specific drugs for effectively controlling infection, it is necessary to further understand the relationship between host and CSFV. Numerous studies related to the mechanism of CSFV replication have been performed, the pathogenesis of CSFV is still poorly understood
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