Modification of Helicobacter pylori Peptidoglycan Enhances NOD1 Activation and Promotes Cancer of the Stomach

Abstract

Helicobacter pylori is the strongest known risk factor for gastric carcinogenesis. One cancer-linked locus is the cag pathogenicity island, which translocates components of peptidoglycan (PGN) into host cells. NOD1 is an intracellular immune receptor that senses PGN from Gram-negative bacteria and responds by inducing autophagy and activating NF-κB, leading to inflammation-mediated bacterial clearance; however chronic pathogens can evade NOD1-mediated clearance by altering PGN structure. We previously demonstrated that the H. pylori cag+ strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. Using 2D-DIGE and mass spectrometry, we identified a novel mutation within the gene encoding the peptidoglycan deacetylase PgdA; therefore, we sought to define the role of H. pylori PgdA in NOD1-dependent activation of NF-κB, inflammation, and cancer. Co-culture of H. pylori strain 7.13 or its pgdA− isogenic mutant with AGS gastric epithelial cells or HEK293 epithelial cells expressing a NF-κB reporter revealed that pgdA inactivation significantly decreased NOD1-dependent NF-κB activation and autophagy. Infection of Mongolian gerbils with an H. pylori pgdA− mutant strain led to significantly decreased levels of inflammation and malignant lesions in the stomach; however, pre-activation of NOD1 prior to bacterial challenge reciprocally suppressed inflammation and cancer in response to wild-type H. pylori. Expression of NOD1 differs in human gastric cancer specimens compared to non-cancer samples harvested from the same patients. These results indicate that PGN deacetylation plays an important role in modulating host inflammatory responses to H. pylori, allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche.

Cdx2 Expression and Intestinal Metaplasia Induced by H. pylori Infection of Gastric Cells Is Regulated by NOD1-Mediated Innate Immune Responses

“…The protective effect has been demonstrated in studies showing that type I interferon responses induced by NOD1 stimulation reduce the level of H. pylori infection (8) and that β-defensin production induced by NOD1 exerts a negative influence on H. pylori survival (38). The reciprocal proinflammatory effect has been shown in studies showing that NOD1 signaling enhances epithelial chemokine responses and that an H. pylori organism bearing a mutation in its NOD1-stimulating peptidoglycan induces decreased inflammation and malignant transformation in vivo (39). These negative and positive effects on H. pylori –induced inflammation, however, are probably independent from the effects of NOD1 on Cdx2 expression reported here, as the latter influences malignant transformation in gastric tissue harboring a chronic and stable infection.…”

Aconitase Functions as a Pleiotropic Posttranscriptional Regulator in Helicobacter pylori

“…Recently, our laboratory demonstrated that H. pylori apo-AcnB binds to the 3= UTR of the peptidoglycan deacetylase (pgdA) transcript, resulting in transcript stability and increased PgdA expression (5). PgdA confers lysozyme resistance and immune evasion; its expression is increased when H. pylori cells are exposed to oxidative stress or are in contact with host immune cells (19)(20)(21)(22). AcnB plays an important role in the posttranscriptional regulation of PgdA (5).…”

Bacterial xenophagy and its possible role in cancer: A potential antimicrobial strategy for cancer prevention and treatment

“…2). 74 Moreover, xenophagy appears to be a pivotal mechanism involved in H. pylori recognition and H. pylori-related gastric cancer. The highly virulent H. pylori strain GC026 that is associated with gastric cancer can markedly downregulate xenophagy in AGS cells.…”