Influence of polymorphisms in porcine N0D2 on ligand recognition

摘要

Nucleotide oligomerization domain 2 (N0D2) is a cytosolic pattern recognition receptor (PRR) ttiat responds to muramyldipeptide (MDP), a component of peptidoglycans of Gram positive and negative bacteria. N0D2 is involved in the modulation of signaling pathways for other PRRs, such as Toll-like receptors. Polymorphisms in N0D2 may evoke bowel disorders, and human Crohn's disease is significantly correlated with mis-sense insertion of the N0D2 gene. Such polymorphisms affecting ligand recognition in the N0D2 gene may also influence bowel flora in livestock, which is compromised by bowel diseases such as diarrhea. We investigated the functional variance of mis-sense polymorphisms in ligand recognition by porcine N0D2. The 1949T>C polymorphism, located in the region encoding the hinge domain of the molecule, notably diminished the functional response of porcine N0D2 to MDP. By comparison, the 2197A>C polymorphism, localized in the region corresponding to leucine-rich repeats, significantly augmented the response of porcine N0D2 to the ligand. The 1949C allele was rare among pig breeds, suggesting that this mutation is a disadvantage to pigs in their immune response to microbes. The 2197C allele, in contrast, was widely distributed among Western breeds and is most likely to be derived from wild boars in Asia. This is the first report of a causal relationship between molecular function and polymorphisms in PRRs in non-primate, non-rodent mammals. These findings suggest that the 2197C allele might confer an immune response advantage in modern pig breeds and may be a useful marker for breeding aimed at disease resistance in pigs.