Genetic variation of toll-like receptor genes and infection by Mycobacterium avium ssp. paratuberculosis in Holstein-Friesian cattle

Abstract

Toll-like receptors (TLR) are membrane proteins that play a key role in innate immunity, by recognizing pathogens and subsequently activating appropriate responses. Mutations in TLR genes are associated with susceptibility to inflammatory and infectious diseases in humans. In cattle, 3 members of the TLR family, TLR1, TLR2, and TLR4, are associated with Mycobacterium avium ssp. paratuberculosis infection, although the extent of this association for the TLR1 and TLR4 receptors has not yet been determined. Moreover, the causal variant in the TLR2 gene has not yet been unequivocally established. In this study, 24 single nucleotide polymorphisms (SNP) in the bovine TLR1, TLR2, and TLR4 genes were selected from the literature, databases, and in silico searches, for a population-based genetic association study of a Spanish Holstein-Friesian sample. Whereas previous results regarding the TLR1 gene were not corroborated, a risk haplotype was detected in TLR2; however, its low frequency indicates that this detected association should be interpreted with caution. In the case of the TLR4 gene, 3 tightly linked SNP were found to be associated with susceptibility to M. avium ssp. paratuberculosis infection. Moreover, one of these SNP, the SNP c.-226G>C, which is localized in the 5'UTR region of the TLR4 gene, has been reported to be able to alter TLR4 expression, raising the possibility that this mutation may contribute to the response of the individual to infection.

Single nucleotide polymorphisms in immunity-related genes and their association with mastitis in Chilean dairy cattle

“…This variant (G) was also predominant in a Canadian Holstein bull population studied by Sharma et al (2006), who also found an association between the C allele, higher SCS, and higher lactation persistence. This SNP has also been implicated in the susceptibility to paratuberculosis (Ruiz-Larrañaga et al, 2011). Although SCS has previously been genetically correlated with clinical mastitis (albeit not definitively) and has been used as an indicator of mastitis and exploited for selecting animals with mastitis resistance (Koivula et al, 2005), no association between SCS and genotype or sanitation status was found in our analyses.…”

Genetic Association Analysis of Paratuberculosis Forms in Holstein-Friesian Cattle

“…Since the characterization of this PTB form is most closely related to those forms of infection which include shedding MAP in feces and testing positive to the ELISA test [25], one could assume a relative similarity to those animals defined as cases in our previous studies [5–8] and therefore expect to confirm those already associated SNPs. In this sense, several causes could explain the lack of positive association results on this occasion.…”

“…In this sense, several causes could explain the lack of positive association results on this occasion. As mentioned above, our preliminary case-control association studies aimed to identify genetic variations related to microbiological and/or immunological evidences of infection [5–8], while, in this paper, histopathological observation was used for determining the phenotypical categories. Additionally, in those previous works phenotypical classification strongly leaned on classifying as uninfected controls only those animals that had tested negative in microbiological and immunological diagnostic methods.…”

“…Previous case-control studies in cattle have concluded diverse associations between genetic variants in innate immunity-related genes and PTB status, which made marker-assisted selection (MAS) a promising tool to improve PTB control. Among those susceptibility loci , some located in the nucleotide-binding oligomerization domain 2 (NOD2), solute carrier family 11 member A1 (SLC11A1), nuclear body protein SP110 (SP110), and toll-like receptors (TLRs) 2 and 4 genes have been previously identified by our group in a Spanish Holstein-Friesian population [5–8]. Additionally, we have recently found five SNPs in CD209 (also known as DC-SIGN, dendritic cell-specific ICAM3-grabbing nonintegrin ) showing epistatic interactions with TLR2 and TLR4 genes among MAP infected cattle, which would support the implication of this gene on mycobacterial recognition and the onset of innate and adaptive immune responses against it [9, 10].…”

Altered Toll-Like Receptor 9 Signaling in Mycobacterium avium subsp. paratuberculosis-Infected Bovine Monocytes Reveals Potential Therapeutic Targets

“…Mutations of the TLR system are associated with increased sensitivity to infection by M. avium subsp. paratuberculosis (20,21). Altered levels of TLR expression during natural M. avium subsp.…”