Helicobacter pylori (H. pylori) is the strongest known risk factor for gastric 
carcinogenesis. One cancer-linked locus is the cag pathogenicity island, which 
translocates components of peptidoglycan into host cells. NOD1 is an 
intracellular immune receptor that senses peptidoglycan 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 peptidoglycan 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. Coculture 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, preactivation of NOD1 before bacterial challenge reciprocally 
suppressed inflammation and cancer in response to wild-type H. pylori. 
Expression of NOD1 differs in human gastric cancer specimens compared with 
noncancer samples harvested from the same patients. These results indicate that 
peptidoglycan 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.