Identifying and exploiting the molecular basis of resistance to gastro-intestinal nematodes in sheep

Abstract

Teladorsagia circumcincta is a common parasitic nematode of the sheep abomasum, causing reduced growth in young lambs. The widespread development of anthelmintic resistant parasites has driven the need for alternative control strategies. Resistant immunity is acquired through repeated exposure to the parasite. The immune response and clinical outcome vary greatly between animals, but resistance is heritable. The aims of this project were: 1) understand how sheep respond to nematode infection; 2) understand and identify genes associated with the response; 3) identify variation within those genes which may contribute to resistance. Using an artificially infected animal model, transcriptomic analysis in resistant and susceptible lambs identified genes involved in T helper cell polarization as integral to disease outcome. T helper cell (Th)1 and Th17 activation was associated with susceptibility (low antibody, high worm numbers) while a Th2 response was associated with resistance (high antibody levels and clearance of infection). The Th cell transcription factors (GATA3, TBX21, RORC2 and RORA) were sequenced with splice variants and SNPs identified. Analysis of gene expression in the abomasal lymph node identified RORAv2 as associated with susceptibility and RORAv5 as associated with resistance. In the abomasal mucosa, GATA3 expression was linked to resistance. Expression analysis of cytokine receptors expressed by Th cells identified IL17RB and IL17RBv2 as associated with resistance in the abomasal mucosa. Analysis of the SNPs within these genes in 3 naturally infected populations identified a significant association between SNPs in IL23R with weight and FEC. This project has provided an in-depth analysis of the ovine transcriptome and identified several genes associated with the development of resistance to nematodes.