Nod1 and Nod2 Regulation of Inflammation in the
            <i>Salmonella</i>
            Colitis Model

Geddes, Kaoru; Rubino, Stephen; Streutker, Catherine; Cho, Joon Ho; Magalhães, João G.; Bourhis, Lionel Le; Selvanantham, Thirumahal; Girardin, Stephen E.; Philpott, Dana J.

doi:10.1128/iai.00759-10

Cited by 115 publications

(104 citation statements)

References 43 publications

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“…Mice deficient in either NOD1 or NOD2 were not susceptible to infection, but mice deficient in both NOD1 and NOD2 exhibited increased Salmonella colonization of the intestine (16). Similarly, it appears that for HCMV, collaboration between NOD1 and NOD2 may have an additive effect in virus suppression, with NOD1 activation inducing an early tier of innate immune response, followed by a second tier through NOD2.…”

Section: Discussionmentioning

confidence: 97%

“…RIPK2's role in NOD-dependent induction of innate and adaptive immunity has been reported previously (15). For some intracellular bacteria, collaboration between NOD1 and NOD2, rather than individual activation of each receptor, is important in host response (16). In addition, induction of tolerance to NOD2 activities resulted in increased activation of NF-κB in response to an NOD1 agonist, suggesting that crosstolerization between NOD1 and NOD2 may result in improved recognition of bacteria (17)(18)(19).…”

Section: Significancementioning

confidence: 99%

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Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo

Fan

Roy

Mukhopadhyay

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Induction of nucleotide-binding oligomerization domain 2 (NOD2) and downstream receptor-interacting serine/threonine-protein kinase 2 (RIPK2) by human cytomegalovirus (HCMV) is known to up-regulate antiviral responses and suppress virus replication. We investigated the role of nucleotide-binding oligomerization domain 1 (NOD1), which also signals through RIPK2, in HCMV control. NOD1 activation by Tri-DAP (NOD1 agonist) suppressed HCMV and induced IFN-β. Mouse CMV was also inhibited through NOD1 activation. NOD1 knockdown (KD) or inhibition of its activity with small molecule ML130 enhanced HCMV replication in vitro. NOD1 mutations displayed differential effects on HCMV replication and antiviral responses. In cells overexpressing the E56K mutation in the caspase activation and recruitment domain, virus replication was enhanced, but in cells overexpressing the E266K mutation in the nucleotidebinding domain or the wild-type NOD1, HCMV was inhibited, changes that correlated with IFN-β expression. The interaction of NOD1 and RIPK2 determined the outcome of virus replication, as evidenced by enhanced virus growth in NOD1 E56K mutant cells (which failed to interact with RIPK2). NOD1 activities were executed through IFN-β, given that IFN-β KD reduced the inhibitory effect of Tri-DAP on HCMV. Signaling through NOD1 resulting in HCMV suppression was IKKα-dependent and correlated with nuclear translocation and phosphorylation of IRF3. Finally, NOD1 polymorphisms were significantly associated with the risk of HCMV infection in women who were infected with HCMV during participation in a glycoprotein B vaccine trial. Collectively, our data indicate a role for NOD1 in HCMV control via RIPK2-IKKα-IRF3 and suggest that its polymorphisms predict the risk of infection.H uman cytomegalovirus (HCMV), a member of the herpesvirus family, induces complex innate immune responses (1, 2). Despite this effective and multifaceted induction, HCMV has developed strategies to counteract its recognition (3), allowing for its productive replication and the establishment of latency. Identification and characterization of HCMV-induced innate immune responses and resulting signaling pathways may provide novel strategies for its control.Mounting evidence indicates that HCMV sensing is an intricate process involving activities of membrane, cytoplasmic, and nuclear receptors. Several HCMV-encoded proteins directly activate innate immune response molecules; the glycoprotein B (gB) binds to and activates TLR2 (4), and pp65 interacts with IFI16 (5). Other viral proteins, dsDNA, or dsRNA are likely to activate or inhibit host innate response molecules. Several previous reports have highlighted a complex role of the IFN pathway in response to HCMV. The activity of the promyeolcytic leukemia protein, a regulator of type I IFN response, is counteracted by HCMV-encoded immediate early 1 protein (IE1) (6). A cytoplasmic dsDNA sensor, ZBP1, activates IRF3 on infection, and its overexpression inhibits HCMV replication (7). IFN-inducible protein IFI16 modestly in...

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Section: Discussionmentioning

confidence: 97%

Section: Significancementioning

confidence: 99%

Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo

Fan

Roy

Mukhopadhyay

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Mutations in Nod1 and Nod2 in humans have been associated with inflammatory disorders, such as asthma and Crohn's disease, respectively (41,42). Nod1 and Nod2 are key bacteria-sensing receptors and are important in the early response against enteric pathogens, including S. typhimurium and Citrobacter rodentium (43,44).…”

mentioning

confidence: 99%

Nod1 and Nod2 Enhance TLR-Mediated Invariant NKT Cell Activation during Bacterial Infection

Selvanantham

Escalante

Tleugabulova

et al. 2013

The Journal of Immunology

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Invariant NKT (iNKT) cells act at the crossroad between innate and adaptive immunity and are important players in the defense against microbial pathogens. iNKT cells can detect pathogens that trigger innate receptors (e.g., TLRs, Rig-I, Dectin-1) within APCs, with the consequential induction of CD1d-mediated Ag presentation and release of proinflammatory cytokines. We show that the cytosolic peptidoglycan-sensing receptors Nod1 and Nod2 are necessary for optimal IFN-γ production by iNKT cells, as well as NK cells. In the absence of Nod1 and Nod2, iNKT cells had a blunted IFN-γ response following infection by Salmonella enterica serovar Typhimurium and Listeria monocytogenes. For Gram-negative bacteria, we reveal a synergy between Nod1/2 and TLR4 in dendritic cells that potentiates IL-12 production and, ultimately, activates iNKT cells. These findings suggest that multiple innate pathways can cooperate to regulate iNKT cell activation during bacterial infection.

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“…Nod2 knockout mice suffered from an impaired bacterial clearance after exposing with pathogens, e.g. [99][100][101][102]. The increased bacterial colonization indicates a crucial role for NOD2 in the bacterial clearance.…”

Section: The Mdp-nod2 Pathway In Mucosal Immunitymentioning

confidence: 99%

Muramyl dipeptide responsive pathways in Crohn’s disease: from NOD2 and beyond

Salem

Seidelin

Rogler

et al. 2012

Cell. Mol. Life Sci.

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Crohn's disease (CD) is one of main disease entities under the umbrella term chronic inflammatory bowel disease. The etiology of CD involves alterations in genetic, microbiological, and immunological factors. This review is devoted to the role of the bacterial wall compound muramyl dipeptide (MDP) for the activation of inflammatory pathways involved in the pathogenesis of CD. The importance of this molecule is underscored by the fact that (1) MDP, which is found in most Gram-negative and -positive bacteria, is able to trigger several immunological responses in the intestinal system, and (2) that alterations in several mediators of the MDP response including-but not restricted to-nucleotide oligomerization domain 2 (NOD2) are associated with CD. The normalization of MDP signaling is one of several important factors that influence the intestinal inflammatory response, a fact which emphasizes the pathogenic importance of MDP signaling for the pathogenesis of CD. The important aspects of NOD2 and non-NOD2 mediated effects of MDP for the development of CD are highlighted, as well as how alterations in these pathways might translate into the development of new therapeutic strategies.

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Nod1 and Nod2 Regulation of Inflammation in the Salmonella Colitis Model

Cited by 115 publications

References 43 publications

Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo

Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo

Nod1 and Nod2 Enhance TLR-Mediated Invariant NKT Cell Activation during Bacterial Infection

Muramyl dipeptide responsive pathways in Crohn’s disease: from NOD2 and beyond

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