Species‐specific engagement of human nucleotide oligomerization domain 2 ( NOD )2 and T oll‐like receptor ( TLR ) signalling upon intracellular bacterial infection: role of C rohn's associated NOD 2 gene variants

Summary Recognition of bacterial peptidoglycan‐derived muramyl‐dipeptide ( MDP ) by nucleotide oligomerization domain 2 ( NOD 2) induces crucial innate immune responses. Most bacteria carry the N ‐acetylated form of MDP ( A ‐ MDP ) in their cell membranes, whereas N ‐glycolyl MDP ( G ‐ MDP ) is typical for mycobacteria. Experimental murine studies have reported G ‐ MDP to have a greater NOD 2‐stimulating capacity than A ‐ MDP . As NOD 2 polymorphisms are associated with C rohn's disease ( CD ), a link has been suggested between mycobacterial infections and CD . Thus, the aim was to investigate if NOD 2 responses are dependent upon type of MDP and further to determine the role of NOD 2 gene variants for the bacterial recognition in CD . The response pattern to A ‐ MDP , G ‐ MDP , M ycobacterium segmatis (expressing mainly G ‐ MDP ) and M . segmatisΔnam H (expressing A ‐ MDP ), L isteria monocytogenes ( LM ) (an A ‐ MDP ‐containing bacteria) and M. avium paratuberculosis ( MAP ) (a G ‐ MDP ‐containing bacteria associated with CD ) was investigated in human peripheral blood mononuclear cells ( PBMC s). A‐ MDP and M . segmatisΔnam H induced significantly higher tumour necrosis factor ( TNF )‐α protein levels in healthy wild‐type NOD 2   PBMC s compared with G ‐ MDP and M . segmatis . NOD 2 mutations resulted in a low tumour necrosis factor ( TNF )‐α protein secretion following stimulation with LM . Contrary to this, TNF ‐α levels were unchanged upon MAP stimulation regardless of NOD 2 genotype and MAP solely activated NOD 2‐ and T oll‐like receptor ( TLR s)‐pathway with an enhanced production of interleukin ( IL )‐1β and IL ‐10. In conclusion, the results indicate that CD ‐associated NOD 2 deficiencies might affect the response towards a broader array of commensal and pathogenic bacteria expressing A ‐ MDP , whereas they attenuate the role of mycobacteria in the pathogenesis of CD .