Abstract:
Paratuberculosis is a chronic intestinal infection in ruminants, caused by Mycobacterium
avium subspecies paratuberculosis (Map). To study the role of host genetics in disease
susceptibility, the Toll-like receptor 2 (TLR2) gene, selected based on its potential role in
immunity to mycobacterial infections, was analyzed for single nucleotide polymorphisms
(SNP) and their potential association with disease.
For SNP discovery and to study SNP association with disease, a case–control study
including 24 cows from farms with paratuberculosis was conducted. Sequence analysis
of the TLR2 genes from 12 paratuberculosis-infected animals and 12 age-matched
healthy herd mates revealed 21 different SNP. The TLR2-1903 T/C SNP was significantly
associated with resistance to Map. This and four additional TLR2 SNP were studied in a
subsequent observational field study with 553 cows from farms with paratuberculosis.
The allelic distribution of the TLR2-1903 T/C SNP was confirmed to be significantly
different between the infected and non-infected animals. For the TLR2-1903 T/C SNP
the odds ratio was calculated, and similar to the dominance model in the association
study, the CT and CC genotypes were compared to the TT genotype. Cows with the
TLR2-1903 T/C mutation (i.e., the CT and CC genotypes) were at 1.7 (95% CI: 1.2, 2.8)
times the odds of being Map-infected compared to cows with the TT genotype. In in
vitro functional assays, monocyte-derived macrophages from animals with a TLR2-
1903 TT genotype produced more IL12p40 and IL1b when stimulated with Map
compared to cells derived from TLR2-1903 CT and CC genotypes. Also, T cell
proliferative responses to mycobacterial antigens were higher in animals with a TLR2-
1903 TT genotype.
