Integrative Network Analysis of Predicted miRNA-Targets Regulating Expression of Immune Response Genes in Bovine Coronavirus Infection

Abstract

Bovine coronavirus (BCoV) infection that causes disease outbreaks among farm animals, resulting in significant economic losses particularly in the cattle industry, has the potential to become zoonotic. miRNAs, which are short non-coding segments of RNA that inhibits the expression of their target genes, have been identified as potential biomarkers and drug targets, though this potential in BCoV remains largely unknown. We hypothesize that certain miRNAs could simultaneously target multiple genes, are significantly conserved across many species, thereby demonstrating the potential to serve as diagnostic or therapeutic tools for bovine coronavirus infection. To this end, we utilized different existing and publicly available computational tools to conduct system analysis predicting important miRNAs that could affect BCoV pathogenesis. Eleven genes including CEBPD, IRF1, TLR9, SRC, and RHOA, significantly indicated in immune-related pathways, were identified to be associated with BCoV, and implicated in other coronaviruses. Of the 70 miRNAs predicted to target the identified genes, four concomitant miRNAs (bta-miR-11975, bta-miR-11976, bta-miR-22-3p, and bta-miR-2325c) were found. Examining the gene interaction network suggests IL-6, IRF1, and TP53 as key drivers. Phylogenetic analysis revealed that miR-22 was completely conserved across all 14 species it was searched against, suggesting a shared and important functional role. Functional annotation and associated pathways of target genes, such as positive regulation of cytokine production, IL-6 signaling pathway, and regulation of leukocyte differentiation, indicate the miRNAs are major participants in multiple aspects of both innate and adaptive immune response. Examination of variants evinced a potentially deleterious SNP in bta-miR-22-3p and an advantageous SNP in bta-miR-2325c. Conclusively, this study provides new insight into miRNAs regulating genes responding to BCoV infection, with bta-miR-22-3p particularly indicated as a potential drug target or diagnostic marker for bovine coronavirus.

Integrative COVID-19 Biological Network Inference with Probabilistic Core Decomposition

“…For SRC (Proto-oncogene tyrosine-protein kinase Src), in Lin et al [31], ibrutinib is found to block SRC family kinases, which might reduce viral entry as well as the inflammatory cytokine response in the lungs. Morenikeji et al [32] identified SRC to be one of the genes associated with Bovine coronavirus and by implication, other coronaviruses. Tiwari et al [33] found SRC to play a vital role in SARS-CoV-2 infection related pathways.…”

Regulatory Network of MiRNAs, IncRNAs, Transcription Factors and Target Genes Associated With Immune Response in Bovine Mastitis

“…The analytical pipeline employed for this study, starting from literature search to interaction networks (Fig. 1a), including some amendments has been described previously [7,54]. Brie y, to obtain experimentally validated genes associated with bovine mastitis, we carried out an extensive search for signi cantly mentioned genes, utilizing several databases.…”

“…To do this, we predicted the possible miRNA binding sites on the lncRNA sequences and determine their normalized binding free energy (ndG) based on the complementary base pairing, using LncTar [19]. Furthermore, miRNA, lncRNA, their target genes, and the biological processes were connected on a critical network using Cytoscape version 3.7.2, as described previously [54,65].…”

Regulatory Network of miRNA, lncRNA, Transcription Factor and Target Immune Response Genes in Bovine Mastitis

“…The analytical pipeline employed for this study, starting from literature search to interaction networks (Fig 1a), including some modi cations have been described previously 7,54 . Brie y, to obtain experimentally validated genes associated with bovine mastitis, we carried out an extensive search for signi cantly mentioned genes, utilizing several databases.…”

“…To do this, we predicted the possible miRNA binding sites on the lncRNA sequences and determine their normalized binding free energy (ndG) based on the complementary base pairing, using LncTar 19 . Furthermore, miRNA, lncRNA, their target genes, and the biological processes were connected on a critical network using Cytoscape version 3.7.2, as described previously 54,65 .…”