|Wu, Sitao - University Of California|
|Li, Weizhong - University Of California|
|Schroeder, Steven - Steve|
Submitted to: Veterinary Parasitology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/9/2015
Publication Date: 5/18/2015
Citation: Li, R.W., Wu, S., Li, C., Li, W., Schroeder, S.G. 2015. Splice variants and regulatory networks associated with host resistance to the intestinal worm Cooperia oncophora in cattle. Veterinary Parasitology. DOI:10.1016/j.vetpar.2015.05.010.
Interpretive Summary: Intestinal worms of the genus Cooperia are among the most dominant parasite species infecting cattle in temperate climates. Infection by these parasites in cattle reduces bodyweight gain up to 14% and negatively impacts carcass quality and reproductive performance. In this study, we characterized jejunal transcriptome dynamics in Angus heifers selected for parasite resistance for over 20 years and identified biological pathways, novel splice variants, gene fusion events, and regulatory networks that may be related to the development of parasite resistance. Our findings provide insights into the molecular mechanisms of host resistance in cattle. Experimentally validated gene networks are likely to serve as quality therapeutic targets. Moreover, cell adhesion molecules and parasite-specific carbohydrate moieties can be exploited in vaccine development.
Technical Abstract: To elucidate the molecular mechanisms of host resistance, we characterized the jejunal transcriptome of Angus cattle selected for parasite resistance for over 20 years in response to infection caused by the intestinal worm Cooperia oncophora. The transcript abundance of 56 genes, such as that of mucin 12 (MUC12) and intestinal alkaline phosphatase (ALPI), was significantly higher in resistant cattle. Novel splicing variants, exon skipping events, and gene fusion events, were also detected. An algorithm for the reconstruction of accurate cellular networks (ARACNE) was used to infer de novo regulatory molecular networks in the interactome between the parasite and host. Under a combined cutoff of an error tolerance (e = 0.10) and a stringent P-value threshold of mutual information (1.0 x 10^-5), a total of 229,100 direct interactions controlled by 20,288 hub genes were identified. Among these hub genes, 7,651 genes had 100 direct neighbors while the top 9,778 hub genes controlled more than 50% on total direct interactions. Three lysozyme genes (LYZ1, LYZ2, and LYZ3), which are co-located in bovine chromosome 5 in tandem and are strongly upregulated in resistant cattle, shared a common regulatory network of 55 genes. These ancient antimicrobials were likely involved in regulating host–parasite interactions by affecting the gut microbiome. Notably, ALPI, known as a gut mucosal defense factor, controlled a molecular network consisting 410 genes, including 14 transcription factors (TFs) and 10 genes that were significantly regulated in resistant cattle. Several large regulatory networks were controlled by TFs, such as STAT6, SREBF1, and ELF4. Gene ontology (GO) processes significantly enriched in the regulatory network controlled by STAT6 included lipid metabolism. Our findings provide insights into the immune regulation of host–parasite interactions and the molecular mechanisms of host resistance in cattle.