Activation of type I IFN signaling by NOD1 mediates mucosal host defense against<i>Helicobacter pylori</i>infection

Watanabe, Tomohiro; Asano, Naoki; Kitani, Atsushi; Fuss, Ivan J.; Chiba, Tsutomu; Strober, Warren

doi:10.4161/gmic.2.1.15162

Cited by 31 publications

(29 citation statements)

References 32 publications

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“…The nucleotide-binding domain (NBD) and leucine-rich repeatcontaining family (NLR) of receptors were originally reported to induce the NF-κB pathway in response to bacterial pathogens, but more recently induction of alternative signaling reminiscent of antiviral responses, including the IFN pathway and autophagy, have been reported (9)(10)(11). NLRC5 was found to be induced by HCMV within 24 h, and its knockdown (KD) impaired the up-regulation of IFN-α in response to HCMV (12).…”

Section: Ripk2mentioning

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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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: Ripk2mentioning

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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“…NOD1 has been shown to regulate H. pylori infection in gastric epithelial cells 23 and in vivo, H. pylori gastric infection of NOD1 −/− mice resulted in reduced production of IFN‐β and IRGs (such as, IP‐10 ) in the mucosal epithelium. In agreement, mice lacking Ifnar1 have increased susceptibility to H. pylori infection, 24 suggesting that IFN‐β induced via the NOD1 pathway is important in certain bacterial infections 25 …”

Section: Pathogen Recognition At the Mucosamentioning

confidence: 83%

Type I interferons in regulation of mucosal immunity

Mangan

Fung

2012

Immunol Cell Biol

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The mucosal system is the first line of defense against many pathogens. It is continuously exposed to dietary and microbial antigens, and thus the host must maintain a homeostatic environment between commensal microbiota and pathogenic infections. Following infections and inflammatory events, a rapid innate immune response is evoked to dampen the inflammatory processes. Type I interferons, a family of pleiotropic cytokines and major products of the innate immune response, have a key role in these early immune events at the mucosa, as reviewed here. With the emergence of new discoveries of immune cell types in mucosal tissues and their reactions to commensal and pathogenic organisms, we also review the opportunities for exciting research in this field.

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“…The H. pylori peptidoglycan, following the delivery into the epithelial cells through the type IV secretion system or via the outer membrane vesicles secreted from the bacterium, is recognized by NOD1 [74]. Furthermore, a coordination between TLR2 and NOD2 has been reported in H. pylori-infected…”

Section: Accepted Manuscriptmentioning

confidence: 98%

Toll-like receptor 2: An important immunomodulatory molecule during Helicobacter pylori infection

et al. 2017

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Activation of type I IFN signaling by NOD1 mediates mucosal host defense againstHelicobacter pyloriinfection

Cited by 31 publications

References 32 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

Type I interferons in regulation of mucosal immunity

Toll-like receptor 2: An important immunomodulatory molecule during Helicobacter pylori infection

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