Chlamydial species are common intracellular parasites that cause various diseases, mainly characterized by persistent infection, which lead to inflammatory responses modulated by pattern recognition ...receptors (PRRs). The best understood PRRs are the extracellular Toll-like receptors, but recent significant advances have focused on two important proteins, NOD1 and NOD2, which are members of the intracellular nucleotide-binding oligomerization domain receptor family and are capable of triggering the host innate immune signaling pathways. This results in the production of pro-inflammatory cytokines, which is vital for an adequate host defense against intracellular chlamydial infection. NOD1/2 ligands are known to derive from peptidoglycan, and the latest research has resolved the paradox of whether chlamydial species possess this bacterial cell wall component; this finding is likely to promote in-depth investigations into the interaction between the NOD proteins and chlamydial pathogens. In this review, we summarize the basic characteristics and signal transduction functions of NOD1 and NOD2 and highlight the new research on the roles of NOD1 and NOD2 in the host defense against chlamydial infection.
This review summarizes the basic characteristics and signal transduction functions of NOD1 and NOD2 and highlights the roles of NOD1 and NOD2 in the host defense against chlamydial infection.
Mammalian Nod2 is an intracellular protein that is implicated in the innate immune response to the bacterial cell wall and is associated with the development of Crohn’s disease, Blau syndrome, and ...gastrointestinal cancers. Nod2 is required for an immune response to muramyl dipeptide (MDP), an immunostimulatory fragment of bacterial cell wall, but it is not known whether MDP binds directly to Nod2. We report the expression and purification of human Nod2 from insect cells. Using novel MDP self-assembled monolayers (SAMs), we provide the first biochemical evidence for a direct, high-affinity interaction between Nod2 and MDP.
Nucleotide-binding oligomerization domain 2 (NOD2) is a receptor of the innate immune system that is capable of perceiving bacterial and viral infections. Muramyl dipeptide (MDP, N-acetyl muramyl ...L-alanyl-d-isoglutamine), identified as the minimal immunologically active component of bacterial cell wall peptidoglycan (PGN) is recognized by NOD2. In terms of biological activities, MDP demonstrated vaccine adjuvant activity and stimulated non-specific protection against bacterial, viral, and parasitic infections and cancer. However, MDP has certain drawbacks including pyrogenicity, rapid elimination, and lack of oral bioavailability. Several detailed structure-activity relationship (SAR) studies around MDP scaffolds are being carried out to identify better NOD2 ligands. The present review elaborates a comprehensive SAR summarizing structural aspects of MDP derivatives in relation to NOD2 agonistic activity.
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•Muramyl dipeptide (MDP) is the minimal peptidoglycan structure that activates NOD2.•A detailed SAR on MDP analogs is elaborated.•Desmuramylpeptides lacking sugar moiety are emerging as new class of NOD2 agonists.•Bioconjugation approach is explored to strengthen the immune system against tumor.
Abstract
Background
Inflammatory bowel disease may arise with inadequate immune response to intestinal bacteria. NOD2 is an established gene in Crohn’s disease pathogenesis, with deleterious ...variation associated with reduced NFKB signaling. We hypothesized that deleterious variation across the NOD2 signaling pathway impacts on transcription.
Methods
Treatment-naïve pediatric inflammatory bowel disease patients had ileal biopsies for targeted autoimmune RNA-sequencing and blood for whole exome sequencing collected at diagnostic endoscopy. Utilizing GenePy, a per-individual, per-gene score, genes within the NOD signaling pathway were assigned a quantitative score representing total variant burden. Where multiple genes formed complexes, GenePy scores were summed to create a “complex” score. Normalized transcript expression of 95 genes within this pathway was retrieved. Regression analysis was performed to determine the impact of genomic variation on gene transcription.
Results
Thirty-nine patients were included. Limited clustering of patients based on NOD signaling transcripts was related to underlying genomic variation. Patients harboring deleterious variation in NOD2 had reduced NOD2 (β = -0.702, P = 4.3 × 10-5) and increased NFKBIA (β = 0.486, P = .001), reflecting reduced NFKB signal activation. Deleterious variation in the NOD2-RIPK2 complex was associated with increased NLRP3 (β = 0.8, P = 3.1475 × 10-8) and TXN (β = -0.417, P = 8.4 × 10-5) transcription, components of the NLRP3 inflammasome. Deleterious variation in the TAK1-TAB complex resulted in reduced MAPK14 transcription (β = -0.677, P = 1.7 × 10-5), a key signal transduction protein in the NOD2 signaling cascade and increased IFNA1 (β = 0.479, P = .001), indicating reduced transcription of NFKB activators and alternative interferon transcription in these patients.
Conclusions
Data integration identified perturbation of NOD2 signaling transcription correlated with genomic variation. A hypoimmune NFKB signaling transcription response was observed. Alternative inflammatory pathways were activated and may represent therapeutic targets in specific patients.
Prompt recognition of microbes by cells is critical to eliminate invading pathogens. Some cell-associated pattern recognition receptors (PRRs) recognize and respond to microbial ligands. However, ...others can respond to cellular perturbations, such as damage-associated molecular patterns (DAMPs). Nucleotide oligomerization domains 1 and 2 (NOD1/2) are PRRs that recognize and respond to multiple stimuli of microbial and cellular origin, such as bacterial peptidoglycan, viral infections, parasitic infections, activated Rho GTPases, and endoplasmic reticulum (ER) stress. How NOD1/2 are stimulated by such diverse stimuli is not fully understood but may partly rely on cellular changes during infection that result in ER stress. NOD1/2 are ER stress sensors that facilitate proinflammatory responses for pathogen clearance; thus, NOD1/2 may help mount broad antimicrobial responses through detection of ER stress, which is often induced during a variety of infections. Some pathogens may subvert this response to promote infection through manipulation of NOD1/2 responses to ER stress that lead to apoptosis. Here, we review NOD1/2 stimuli and cellular responses. Furthermore, we discuss pathogen-induced ER stress and how it might potentiate NOD1/2 signaling.
Background Enhanced apoptosis of keratinocytes is the main cause of eczema and spongiosis in patients with the common inflammatory skin disease atopic dermatitis (AD). Objective The aim of the study ...was to investigate molecular mechanisms of AD-related apoptosis of keratinocytes. Methods Primary keratinocytes isolated from patients with AD and healthy donors were used to study apoptosis by using annexin V/7-aminoactinomycin D staining. Illumina mRNA Expression BeadChips, quantitative RT-PCR, and immunofluorescence were used to study gene expression. In silico analysis of candidate genes was performed on genome-wide single nucleotide polymorphism data. Results We demonstrate that keratinocytes of patients with AD exhibit increased IFN-γ–induced apoptosis compared with keratinocytes from healthy subjects. Further mRNA expression analyses revealed differential expression of apoptosis-related genes in AD keratinocytes and skin and the upregulation of immune system–related genes in skin biopsy specimens of chronic AD lesions. Three apoptosis-related genes ( NOD2 , DUSP1 , and ADM ) and 8 genes overexpressed in AD skin lesions ( CCDC109B , CCL5 , CCL8 , IFI35 , LYN , RAB31 , IFITM1 , and IFITM2 ) were induced by IFN-γ in primary keratinocytes. The protein expression of IFITM1, CCL5, and CCL8 was verified in AD skin. In line with the functional studies and AD-related mRNA expression changes, in silico analysis of genome-wide single nucleotide polymorphism data revealed evidence of an association between AD and genetic markers close to or within the IFITM cluster or RAB31 , DUSP1 , and ADM genes. Conclusion Our results demonstrate increased IFN-γ responses in skin of patients with AD and suggest involvement of multiple new apoptosis- and inflammation-related factors in the development of AD.
Summary
The role of symbiotic bacteria in the development of antigen‐specific immunity remains poorly understood. Previous studies showed that sensing of symbiotic bacteria by nucleotide‐binding ...oligomerization domain‐containing protein 2 (Nod2) regulates antibody responses in response to nasal immunization with antigen and cholera toxin (CT). In this study, we examined the role of the microbiota in the adjuvant activity of CT induced after oral immunization with antigen. Germ‐free (GF) mice showed impaired production of antibody responses and T‐cell‐specific cytokines after oral immunization when compared with that observed in conventionally raised mice. Similar to GF mice, Nod2‐deficient mice showed reduced humoral responses upon oral immunization with antigen and CT. Treatment with CT enhanced the production of interleukin‐1β (IL‐1β), but not tumor necrosis factor‐α or IL‐12p40, induced by stimulation of dendritic cells with muramyl dipeptide, the Nod2 ligand. Mechanistically, the enhanced production of IL‐1β induced by muramyl dipeptide and CT stimulation required Nod2 and was mediated by both increased synthesis of pro‐IL‐1β and caspase‐1 activation. Furthermore, antigen‐specific antibody and cytokine responses induced by CT were impaired in orally immunized IL‐1β‐deficient mice. Collectively, our results indicate that Nod2 stimulation by symbiotic bacteria contributes to optimal CT‐mediated antigen‐specific oral vaccination through the induction of IL‐1β production.
Nod2 stimulation by symbiotic bacteria contributes to optimal cholera toxin (CT)‐mediated antigen‐specific oral vaccination. The induction of interleukin‐1β production by bacterial component (Nod2 ligand), and CT is one of the crucial underlying mechanisms.
, a human restricted pathogen, releases inflammatory peptidoglycan (PG) fragments that contribute to the pathophysiology of pelvic inflammatory disease. The genus
is also home to multiple species of ...human- or animal-associated
that form part of the normal microbiota. Here we characterized PG release from the human-associated nonpathogenic species
and
and animal-associated
from macaques and wild mice. An
strain and an
strain were found to release limited amounts of the proinflammatory monomeric PG fragments. However, a single amino acid difference in the PG fragment permease AmpG resulted in increased PG fragment release in a second
strain examined.
isolated from macaques also showed substantial release of PG monomers. The mouse colonizer
exhibited PG fragment release similar to that seen in
with PG monomers being the predominant fragments released. All the human-associated species were able to stimulate NOD1 and NOD2 responses.
was a poor inducer of mouse NOD1, but
mutation increased this response. The ability to genetically manipulate
and examine effects of different PG fragments or differing amounts of PG fragments during mouse colonization will lead to a better understanding of the roles of PG in
infections. Overall, we found that only some nonpathogenic
have diminished release of proinflammatory PG fragments, and there are differences even within a species as to types and amounts of PG fragments released.
was the first susceptibility gene identified for Crohn's disease (CD), one of the major forms of inflammatory bowel disease (IBD). The field of NOD2 research has opened up many questions critical to ...understanding the complexities of microbiota-host interactions. In addition to sensing its specific bacterial components as a cytosolic pattern recognition receptor, NOD2 also appears to shape the colonization of intestinal microbiota. Activated NOD2 triggers downstream signaling cascades exampled by the NF-κB pathway to induce antimicrobial activities, however, defective or loss of NOD2 functions incur a similarly activated inflammatory response. Additional studies have identified the involvement of NOD2 in protection against non-microbiota-related intestinal damages as well as extraintestinal infections. We survey recent molecular and genetic studies of NOD2-mediated bacterial sensing and immunological modulation, and integrate evidence to suggest a highly reciprocal but still poorly understood cross talk between enteric microbiota and host cells.
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