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Senecavirus A- and Non-Infected Cells at Early Stage of Infection: Comparative Metabolomic Profiles.

ABSTRACT: Senecavirus A (SVA), classified into the genus Senecavirus in the family Picornaviridae, causes an infectious disease in pigs. This virus can efficiently replicate in some non-pig-derived cells, such as the BHK cell line and its derivative (BSR-T7/5 cell line). We had recovered a wild-type SVA from its cDNA clone previously, and then uncovered the proteomic profile of SVA-infected BSR-T7/5 cells at 12 h post inoculation (hpi). In order to explore the cellular metabolomics further, the SVA-inoculated BSR-T7/5 cell monolayer was collected at 12 hpi for assay via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The resultant data set was comprehensively analyzed using bioinformatics tools. A total of 451 metabolites were identified using in-house and public databases. Out of these metabolites, sixty-one showed significantly differential values (p value < 0.05). The Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to analyze metabolic pathways of the significantly differential metabolites. There were eighty-one identified KEGG pathways, out of which twenty-seven showed their p values < 0.05. The pyrimidine metabolism revealed the minimum p value and the maximum number of significantly differential metabolites, implying the pyrimidine played a key role in cellular metabolism after SVA infection. SVA replication must rely on the cellular metabolism. The present study on metabolomics would shed light on impacts of SVA-induced multiple interactions among metabolites on cells or even on natural hosts.

SUBMITTER: Liu F

PROVIDER: S-EPMC8776658 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Phosphorylation is a widespread posttranslational modification that regulates numerous biological processes. Viruses can alter the physiological activities of host cells to promote virus particle replication, and manipulating phosphorylation is one of the mechanisms. Senecavirus A (SVA) is the causative agent of porcine idiopathic vesicular disease. Although numerous studies on SVA have been performed, comprehensive phosphoproteomics analysis of SVA infection is lacking. The present study performed a quantitative mass spectrometry-based phosphoproteomics survey of SVA infection in Instituto Biologico-Rim Suino-2 (IBRS-2) cells. Three parallel experiments were performed, and 4,520 phosphosites were quantified on 2,084 proteins. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that many phosphorylated proteins were involved in apoptosis and spliceosome pathways, and subcellular structure localization analysis revealed that more than half were located in the nucleus. Motif analysis of proteins with differentially regulated phosphosites showed that proline, aspartic acid, and glutamic acid were the most abundant residues in the serine motif, while proline and arginine were the most abundant in the threonine motif. Forty phosphosites on 27 proteins were validated by parallel reaction monitoring (PRM) phosphoproteomics, and 30 phosphosites in 21 proteins were verified. Nine proteins with significantly altered phosphosites were further discussed, and eight [SRRM2, CDK13, DDX20, DDX21, BAD, ELAVL1, PDZ-binding kinase (PBK), and STAT3] may play a role in SVA infection. Finally, kinase activity prediction showed 10 kinases' activity was reversed following SVA infection. It is the first phosphoproteomics analysis of SVA infection of IBRS-2 cells, and the results greatly expand our knowledge of SVA infection. The findings provide a basis for studying the interactions of other picornaviruses and their mammalian host cells.

Project description:BackgroundThe risk of adult onset cardiovascular and metabolic (cardiometabolic) disease accrues from early life. Infection is ubiquitous in infancy and induces inflammation, a key cardiometabolic risk factor, but the relationship between infection, inflammation, and metabolic profiles in early childhood remains unexplored. We investigated relationships between infection and plasma metabolomic and lipidomic profiles at age 6 and 12 months, and mediation of these associations by inflammation.MethodsMatched infection, metabolomics, and lipidomics data were generated from 555 infants in a pre-birth longitudinal cohort. Infection data from birth to 12 months were parent-reported (total infections at age 1, 3, 6, 9, and 12 months), inflammation markers (high-sensitivity C-reactive protein [hsCRP]; glycoprotein acetyls [GlycA]) were quantified at 12 months. Metabolic profiles were 12-month plasma nuclear magnetic resonance metabolomics (228 metabolites) and liquid chromatography/mass spectrometry lipidomics (776 lipids). Associations were evaluated with multivariable linear regression models. In secondary analyses, corresponding inflammation and metabolic data from birth (serum) and 6-month (plasma) time points were used.ResultsAt 12 months, more frequent infant infections were associated with adverse metabolomic (elevated inflammation markers, triglycerides and phenylalanine, and lower high-density lipoprotein [HDL] cholesterol and apolipoprotein A1) and lipidomic profiles (elevated phosphatidylethanolamines and lower trihexosylceramides, dehydrocholesteryl esters, and plasmalogens). Similar, more marked, profiles were observed with higher GlycA, but not hsCRP. GlycA mediated a substantial proportion of the relationship between infection and metabolome/lipidome, with hsCRP generally mediating a lower proportion. Analogous relationships were observed between infection and 6-month inflammation, HDL cholesterol, and apolipoprotein A1.ConclusionsInfants with a greater infection burden in the first year of life had proinflammatory and proatherogenic plasma metabolomic/lipidomic profiles at 12 months of age that in adults are indicative of heightened risk of cardiovascular disease, obesity, and type 2 diabetes. These findings suggest potentially modifiable pathways linking early life infection and inflammation with subsequent cardiometabolic risk.FundingThe establishment work and infrastructure for the BIS was provided by the Murdoch Children's Research Institute (MCRI), Deakin University, and Barwon Health. Subsequent funding was secured from National Health and Medical Research Council of Australia (NHMRC), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O'Brien Memorial Asthma Foundation, the Our Women's Our Children's Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Minderoo Foundation, the Ilhan Food Allergy Foundation, GMHBA, Vanguard Investments Australia Ltd, and the Percy Baxter Charitable Trust, Perpetual Trustees. In-kind support was provided by the Cotton On Foundation and CreativeForce. The study sponsors were not involved in the collection, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication. Research at MCRI is supported by the Victorian Government's Operational Infrastructure Support Program. This work was also supported by NHMRC Senior Research Fellowships to ALP (1008396); DB (1064629); and RS (1045161) , NHMRC Investigator Grants to ALP (1110200) and DB (1175744), NHMRC-A*STAR project grant (1149047). TM is supported by an MCRI ECR Fellowship. SB is supported by the Dutch Research Council (452173113).

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Senecavirus A- and Non-Infected Cells at Early Stage of Infection: Comparative Metabolomic Profiles.

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