Serum Lipidomics Analysis of Classical Swine Fever Virus Infection in Piglets and Emerging Role of Free Fatty Acids in Virus Replication in vitro

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.

Immunotherapy of COVID-19 with poly (ADP-ribose) polymerase inhibitors: starting with nicotinamide

“…A decrease in [albumin] of ≥19% can significantly cause the release of bound Trp [ 28 ]. Serum [NEFA] has not been measured in COVID-19 patients, but is known to be elevated in infections with other viral classes, e.g., the flavivirus Dengue [ 42 ], the lentivirus HIV [ 43 ] and the asfivirus, the swine (fever) influenza [ 44 ]. Albumin depletion coupled with NEFA elevation provide the maximum effect on Trp binding and the resultant increase in free Trp availability can enhance the production of Kyn through IDO/TDO and thus provide the substrate for proinflammatory KP metabolite formation [ 26 ].…”

Characterization of the lipidomic profile of BmN cells in response to Bombyx mori cytoplasmic polyhedrosis virus infection

“…It has been shown that infection by some single-stranded RNA(ssRNA) viruses can alter the lipid metabolism and other biological processes of the host cells to facilitate the completion of the virus life cycle ( Sanchez and Lagunoff, 2015 ). Free fatty acids (FFAs), which can be used directly by the body for energy metabolism have been shown to be associated with the life cycle of various RNA viruses, including influenza A virus (IAV) ( Limsuwat et al, 2020 ), classical swine fever virus(CSFV) ( Ma et al, 2019 ), Middle East respiratory syndrome coronavirus (MERS-CoV) ( Yan et al, 2019a ), hepatitis C virus (HCV) ( Hofmann et al, 2018 ), zika virus (ZIKV) ( Queiroz et al, 2019 ) and ebola virus ( Kyle et al, 2019 ). Furthermore, some lipids are produced in the cells and others are imported from extracellular environment ( Limsuwat et al, 2020 ).…”

“…Lipids have also been shown to play important roles in the replication of coxsackievirus B3 ( Wang et al, 2020 ). An increased level fatty acid biosynthesis coupled with accumulation of free fatty acids that are associated with virus replication has been observed in host cells following CSFV infection ( Ma et al, 2019 ). Phosphorylated 5′-adenosine monophosphate-activated protein kinase induced by the infection of porcine reproductive and respiratory syndrome virus can inactivate the fatty acid biosynthesis pathway, playing an antagonistic role in the virus replication ( Long et al, 2019 ).…”

The Network of Interactions Between Classical Swine Fever Virus Nonstructural Protein p7 and Host Proteins

“…VDAC1 could interact with IBDV Ribonucleoprotein (RNPs) and facilitates IBDV replication by enhancing IBDV polymerase activity (Han et al, 2017). In our previous work, we have confirmed that CSFV infection was closely associated with mitochondrial function (Gou et al, 2017;Ma et al, 2019). CSFV infection could induce mitochondrial fission and mitophagy to inhibit host cell apoptosis for persistent infection (Gou et al, 2017).…”