Influence of polymorphisms in the NOD1/CARD4 and NOD2/CARD15 genes on the clinical outcome of Helicobacter pylori infection

Abstract

SummaryHost immune response influences the clinical outcome of Helicobacter pylori infection leading to ulcer disease, gastric carcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. A genetic risk profile for gastric cancer has been identified, but genetic susceptibility to develop MALT lymphoma is still unclear. We investigated the role of NOD1 and NOD2 as intracellular recognition molecules for pathogen-associated molecules in H. pylori infection in vitro and analysed the influence of single nucleotide polymorphisms on susceptibility to ulcer disease and MALT lymphoma. Expression of NOD1 and NOD2 significantly sensitized HEK293 cells to H. pylori -induced NF-k B activation in a cag pathogenicity island ( cag PAI)-dependent manner. In cells carrying the Crohn-associated NOD2 variant R702W the NF-k B response was significantly diminished. NOD1/ NOD2 expression levels were induced in the gastric epithelium in H. pylori -positive patients. No mutations were found to be associated with gastritis or gastric ulcer development. However, the R702W mutation in the NOD2/CARD15 gene was significantly associated with gastric lymphoma. Carrier of the rare allele T had a more than doubled risk to develop lymphoma than controls [odds ratio (OR): 2.4, 95% confidence interval (CI): 1.2-4.6; P < 0.044]. H. pylori -induced upregulation of NOD1 and NOD2 in vivo may play a critical role in the recognition of this common pathogen. A missense mutation in the leucine-rich region of CARD15 is associated with gastric lymphoma.

Nucleotide Oligomerization Domain 1 Enhances IFN-γ Signaling in Gastric Epithelial Cells during Helicobacter pylori Infection and Exacerbates Disease Severity

“…We show that this is a cagPAI-and NOD1-dependent phenomenon, supporting previous studies demonstrating that both host factors are essential for Th1-dependent responses during H. pylori infection (3,31). Furthermore, although a previous small study showed a trend of elevated NOD1 expression in eight H. pylori-infected patients (21), the present work is the first report, to our knowledge, to demonstrate a clear correlation between NOD1 expression and disease severity in the human stomach. The novel finding that the expression levels of the potent antioncogene, IRF1, are regulated in a similar fashion could indicate that inflammatory feedback between innate immune activators, such as NOD1, and the IFN-g signaling pathway (Fig.…”

Olfactomedin 4 down-regulates innate immunity against Helicobacter pylori infection

“…Although it was generally hypothesized that Toll-like receptor (TLR) would be involved in the innate immune recognization of H. pylori, no conclusive evidence for a relevant TLR has been presented (19). Instead, it is proposed that NOD1 and NOD2 in vivo may play a critical role in the recognization of H. pylori (19).…”

“…Although it was generally hypothesized that Toll-like receptor (TLR) would be involved in the innate immune recognization of H. pylori, no conclusive evidence for a relevant TLR has been presented (19). Instead, it is proposed that NOD1 and NOD2 in vivo may play a critical role in the recognization of H. pylori (19). The intracellular NOD-like proteins or receptors are a family of sensors of intracellularly encountered microbial motifs that have emerged as critical components of the innate immune response and of inflammation in mammals (24).…”

“…The expression of NOD1 in gastric epithelial cells confers responsiveness to H. pylori and exerts a protective role against bacterial colonization in a mouse model of H. pylori infection (25). NOD2 also sensitizes epithelial cells to recognize H. pylori in vitro (19). NOD1 activity is regulated by its interacting proteins such as cIAP1/2 (26), SGT1 (27), CENTB (28), and Hsp90 (29).…”

“…sensitizes HEK293 cells to H. pylori-induced NF-κB activation (19). Therefore, we used this system to investigate whether OLFM4 affects NOD1 and NOD2-mediated NF-κB activation induced by SS1 infection.…”