Host Sensing of NonTlr Pamps Lessons from NOD1 and NOD2 Studies

Independently of TLRs, the nucleotide-binding oligomerisation domain proteins 2 and 1 (NOD2 and NOD1; also referred as CARD15 and CARD4, respectively) are cytoplasmic proteins involved in bacterial peptidoglycan (PGN) sensing through the detection of the muropeptide N-acetylmuramic-L-Ala-D-isoGln (MDP; Girardin et al. 2003a; Inohara et al. 2003; Kobayashi et al. 2005) and dipeptide y-D-glutamyl-meso-diaminopimelic acid (iE-DAP; Chamaillard et al. 2003a; Girardin et al. 2003b; Fig. 2). Whereas MDP is a conserved structure shared by almost all Gram-positive and Gram-negative bacteria, the dipeptide iE-DAP is primarily found in Gram-negative bacteria and certain Gram-positive bacteria, such as the food-borne pathogen Listeria monocytogenes. Hence unlike NOD2 that can be considered as a general sensor of bacterial microorganisms, NOD1 detect solely Gram-negative bacteria and a specific subset of Gram-positive bacteria that includes L. monocytogenes. Upon exposure to their respective bacterial agonists, NOD2 and NOD1 oligomerize and the downstream serine-threonine kinase RICK (also called RIP2/RIPK2/CARDIAK) is recruited through homophilic CARDCARD interactions. Once activated the RIP2 signaling pathways leads to the activation of the NF-kB transcription factor through the ubiquitination of the IKKy/NEMO

GlcNac GlcNac MurNac

GlcNac GlcNac MurNac

Fig. 2 NOD1 and NOD2 are the sensing bacterial peptidoglycans

Fig. 2 NOD1 and NOD2 are the sensing bacterial peptidoglycans subunit of the signalosome (Inohara et al. 2000; Ogura et al. 2001b; Kobayashi et al. 2002; Abbott et al. 2004). Recent reports identified also accessory molecules that regulate the Rip2 signaling pathway, such as Erbin, Takl, Grim-19 and Centaurin-betal (Chen et al. 2004; Barnich et al. 2005; McDonald et al. 2005; Yamamoto-Furusho et al. 2006; Fig. 1). Accordingly, mice deficient for NOD1, NOD2 and RICK are highly susceptible to infection by the Gram-positive facultative intracellular pathogen, L. monocytogenes (Kobayashi et al. 2002, 2005). Interestingly whereas Nodi-deficient mice are only susceptible to systemic infection by L. monocytogenes (Chamaillard, unpublished data), Nod2-deficient mice showed an increased susceptibility to orogastric infection by this pathogenic bacterium via the regulation of certain Paneth cells-derived cationic antimicrobial peptides (Kobayashi et al. 2005; Fig. 3). Furthermore, Nod2-deficient mice displayed a severe deficiency in the production of antigen specific immunoglobulin (Kobayashi et al. 2005) and experienced an enhanced release of IL-12 and IL-18, leading to an increased proliferation and survival of CD4+ T cells (Watanabe et al. 2006). Consistently, Nod2-deficient mice and mutant mice bearing the orthologue of the major CD-associated

Fig. 3 Schematic of NOD2 signalling in Paneth cells. A An electron microscopy picture of Paneth cell is represented. B Following exposure to bacterial moieties (1), pathogen-recognition molecules (e.g. NOD2) expressed in Paneth cells regulate the expression (2) of immature a-defensins (3), which are processed (4) and secreted outside the cells to maintain sterility in the lumen of the crypt of Lyberkuhn (5)

Fig. 3 Schematic of NOD2 signalling in Paneth cells. A An electron microscopy picture of Paneth cell is represented. B Following exposure to bacterial moieties (1), pathogen-recognition molecules (e.g. NOD2) expressed in Paneth cells regulate the expression (2) of immature a-defensins (3), which are processed (4) and secreted outside the cells to maintain sterility in the lumen of the crypt of Lyberkuhn (5)

NOD23020ins allele showed increased susceptibility to antigen-specific colitis (Watanabe et al. 2006) and to DSS-induced colitis (Maeda et al. 2005), respectively. More recently, professional immunocytes carrying NOD2 mutations or lacking NOD2, but not NOD1, showed impaired responsiveness to MDP (Inohara et al. 2003; Li et al. 2004; Netea et al. 2005; van Heel et al. 2005), but also to Mycobacterium tuberculosis (Ferwerda et al. 2005). However, NOD2 was dispensable for cytokine production in response to L. monocytogenes, as shown by the normal inflammatory cytokines production of Nod2-deficient macrophages compared with wild-type macrophages. These results indicate an essential role of NOD2 in innate and adaptive immunity at the intestinal mucosal interface. Further, recent reports unravelled a NOD1-dependent sensing of the non-invasive Gram-negative pathogen Helicobacter pilori (Viala et al. 2004), through the detection of muropeptides injected into host cells by a bacterial type IV secretion system. Similarly to the physiological role of NOD2, NOD1 is required for expression of certain ß-defensins by gastric epithelial cells during H. pylori infection (Boughan et al. 2006). However the function of NOD1 in adaptive immunity still remains elusive. Finally, bacterial muropeptides are know to syn-ergistically promote the TLR-dependent production of inflammatory cytokines and chemokines (Chamaillard et al. 2003a; Kobayashi et al. 2005; van Heel et al. 2005a, b), indicating that NOD1 and NOD2 might be crucial in initiating the immune response towards invasive bacteria.

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