Abstract
Glaesserella parasuis (G. parasuis) can elicit serious inflammatory responses and cause meningitis in piglets. Previous epigenetic studies have indicated that alterations in host DNA methylation may modify the inflammatory response to bacterial infection. However, to date, genome-wide analysis of the DNA methylome during meningitis caused by G. parasuis infection is still lacking. In this study, we employed an unbiased approach using deep sequencing to profile the DNA methylome and transcriptome from G. parasuis infected porcine brain (cerebrum) and integrated the data to identify key differential methylation regions/sites involved in the regulation of the inflammatory response. Results showed that DNA methylation patterns and gene expression profiles from porcine brain were changed after G. parasuis infection. The majority of the altered DNA methylation regions were found in the intergenic regions and introns and not associated with CpG islands, with only a low percentage occurring at promoter or exon regions. Integrated analysis of the DNA methylome and transcriptome identified a number of inversely and positively correlated genes between DNA methylation and gene expression, following the criteria of |log2FC| > 0.5, |diffMethy| > 0.1, and P < 0.05. Differential expression and methylation of two significant genes, semaphoring 4D (SEMA4D) and von Willebrand factor A domain containing 1 (VWA1), were validated by qRT-PCR and bisulfite sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses demonstrated that DNA methylation inversely correlated genes in G. parasuis infected porcine brains were mainly involved with cell adhesion molecules (CAMs), bacterial invasion of epithelial cells, RIG-1-like receptor signaling pathways, and hematopoietic cell lineage signaling pathways. In addition, a protein-protein interaction network of differentially methylated genes found potential candidate molecular interactions relevant to the pathology of G. parasuis infection. To the best of our knowledge, this is the first attempt to integrate the DNA methylome and transcriptome data from G. parasuis infected porcine brains. Our findings will help understanding the contribution of genome-wide DNA methylation to the pathogenesis of meningitis in pigs and developing epigenetic biomarkers and therapeutic targets for the treatment of G. parasuis induced meningitis.
Highlights
Glaesserella parasuis (G. parasuis), is a commensal pathogen found in the porcine upper respiratory tract, and can invade the bloodstream and cause polyserositis, arthritis, meningitis, and frequently, pneumonia like symptoms, and is the etiological agent of Glässer’s disease [1]
Whole-genome bisulfite sequencing was performed with the Illumina HiSeq 2500 to explore the global DNA methylation changes associated with the pathology of meningitis induced by G. parasuis
We identified 12,145 (DMRs) that were statistically significant between the two groups, with 4,649 DMRs hypermethylated and 7,496 DMRs hypomethylated in G. parasuis infected porcine brain (P < 0.05) (Supplementary File 5)
Summary
Glaesserella parasuis (G. parasuis), is a commensal pathogen found in the porcine upper respiratory tract, and can invade the bloodstream and cause polyserositis, arthritis, meningitis, and frequently, pneumonia like symptoms, and is the etiological agent of Glässer’s disease [1]. Because of the high morbidity and mortality caused by G. parasuis infection, it has become a major threat to the swine industry throughout the world, and its control and prevention are urgently needed [4]. Bacterial meningitis requires prompt diagnosis and medical treatment but even mortality still occurs regardless of its acute or chronic onset [8, 9]. There remains an incomplete understanding of the pathogenesis and the best methods for the prevention and treatment of bacterial meningitis and further research looking at the pathogenesis of bacterial meningitis is urgently needed. Research on the pathology of bacterial meningitis caused by G. parasuis using an infected porcine model appears to be meaningful for both the porcine industry and human public health
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