title: Species-specific engagement of human nucleotide oligomerization domain 2 (NOD)2 and Toll-like receptor (TLR) signalling upon intracellular bacterial infection: role of Crohn's associated NOD2 gene variants.
abstract: Recognition of bacterial peptidoglycan-derived muramyl-dipeptide (MDP) by nucleotide oligomerization domain 2 (NOD2) 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 NOD2-stimulating capacity than A-MDP. As NOD2 polymorphisms are associated with Crohn's disease (CD), a link has been suggested between mycobacterial infections and CD. Thus, the aim was to investigate if NOD2 responses are dependent upon type of MDP and further to determine the role of NOD2 gene variants for the bacterial recognition in CD. The response pattern to A-MDP, G-MDP, Mycobacterium segmatis (expressing mainly G-MDP) and M. segmatisΔnamH (expressing A-MDP), Listeria 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 (PBMCs). A-MDP and M. segmatisΔnamH induced significantly higher tumour necrosis factor (TNF)-α protein levels in healthy wild-type NOD2 PBMCs compared with G-MDP and M. segmatis. NOD2 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 NOD2 genotype and MAP solely activated NOD2- and Toll-like receptor (TLRs)-pathway with an enhanced production of interleukin (IL)-1β and IL-10. In conclusion, the results indicate that CD-associated NOD2 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.
authors.affiliation: Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Salem
authors.forename: J B
authors.initials: JB
authors.lastname: Seidelin
authors.forename: S
authors.initials: S
authors.lastname: Eickhardt
authors.forename: M
authors.initials: M
authors.lastname: Alhede
authors.forename: G
authors.initials: G
authors.lastname: Rogler
authors.forename: O H
authors.initials: OH
authors.lastname: Nielsen
mesh_terms: D000107:Acetylation; D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000276:immunology*; D002478:Cells, Cultured; D003424:Crohn Disease / Q000209:etiology / Q000276:immunology* / Q000382:microbiology; D016207:Cytokines / Q000378:metabolism; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease; D006018:Glycols / Q000737:chemistry; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D042541:Intracellular Space / Q000382:microbiology; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000382:microbiology; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000150:complications / Q000276:immunology* / Q000382:microbiology; D008213:Lymphocyte Activation / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009164:Mycobacterium Infections / Q000150:complications / Q000276:immunology* / Q000382:microbiology; D016927:Mycobacterium avium subsp. paratuberculosis / Q000276:immunology*; D020102:Mycobacterium smegmatis / Q000235:genetics / Q000276:immunology*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D013045:Species Specificity; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D016207:Cytokines; D006018:Glycols; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D051193:Toll-Like Receptors; D000119:Acetylmuramyl-Alanyl-Isoglutamine
keywords: Crohn's disease; Mycobacterium avium paratuberculosis; autophagy; muramyl dipeptide; nucleotide oligomerization domain 2