Systems Biology–Derived Genetic Signatures of Mastitis in Dairy Cattle: A New Avenue for Drug Repurposing

Abstract

Mastitis, a disease with high incidence worldwide, is the most prevalent and costly disease in the dairy industry. Gram-negative bacteria such as Escherichia coli (E. coli) are assumed to be among the leading agents causing acute severe infection with clinical signs. E. Coli, environmental mastitis pathogens, are the primary etiological agents of bovine mastitis in well-managed dairy farms. Response to E. Coli infection has a complex pattern affected by genetic and environmental parameters. On the other hand, the efficacy of antibiotics and/or anti-inflammatory treatment in E. coli mastitis is still a topic of scientific debate, and studies on the treatment of clinical cases show conflicting results. Unraveling the bio-signature of mastitis in dairy cattle can open new avenues for drug repurposing. In the current research, a novel, semi-supervised heterogeneous label propagation algorithm named Heter-LP, which applies both local and global network features for data integration, was used to potentially identify novel therapeutic avenues for the treatment of E. coli mastitis. Online data repositories relevant to known diseases, drugs, and gene targets, along with other specialized biological information for E. coli mastitis, including critical genes with robust bio-signatures, drugs, and related disorders, were used as input data for analysis with the Heter-LP algorithm. Our research identified novel drugs such as Glibenclamide, Ipratropium, Salbutamol, and Carbidopa as possible therapeutics that could be used against E. coli mastitis. Predicted relationships can be used by pharmaceutical scientists or veterinarians to find commercially efficacious medicines or a combination of two or more active compounds to treat this infectious disease.

Veterinary systems biology for bridging the phenotype–genotype gap via computational modeling for disease epidemiology and animal welfare

“…An integrative systems biology study identified several key genes, such as PRDX5 , RAB5C , ACTN4 , SLC25A16 , MAPK6 , CD53 , NCKAP1L , ARHGEF2 , COL9A1 and PTPRC , as well as pathways involved in the development and progression of mastitis, providing potential targets for future research and therapeutics [ 18 ]. Another study identified new treatment options by repurposing existing drugs Glibenclamide, Ipratropium, Salbutamol and Carbidopa for veterinary medicine against Escherichia coli mastitis [ 106 ]. A system-based analysis at 6, 12 and 24 h post-infection with African swine fever virus (ASFV) revealed 1677, 2122 and 2945 upregulated differentially expressed genes (DEGs), as well as 933, 1148 and 1422 downregulated DEGs, respectively, compared to mock-infected groups.…”

Integrated co-expression analysis of regulatory elements (miRNA, lncRNA, and TFs) in bovine monocytes induced by Str. uberis

“…Furthermore, the role of key genes in the molecular mechanisms of resistance to bovine mastitis 13 and also in predicting drug candidates for the control and management of mastitis has been previously investigated 14 , but the regulatory elements, such as miRNAs, lncRNAs, and TFs, involved in the expression of these genes are not yet fully understood. A growing number of reports suggest a significant utility of miRNAs 15 , lncRNAs 16 , 17 , and TFs 16 as biological markers of pathogenic conditions, modulators of drug resistance, and/or drug development for medical intervention.…”