CagA and Cag type IV secretion system activity have key roles in triggering gastric transcriptional and proteomic alterations.

Colonization of the human stomach with pathogenicity island (PAI)-positive strains is associated with increased gastric cancer risk compared to colonization with PAI-negative strains. To evaluate the contributions of the Cag type IV secretion system (T4SS) and CagA (a secreted bacterial oncoprotein) to gastric molecular alterations relevant for carcinogenesis, we infected Mongolian gerbils with a Cag T4SS-positive wild-type (WT) strain, one of two Cag T4SS mutant strains (∆ or ∆), or a ∆ mutant for 12 weeks. Histologic staining revealed a biphasic distribution of gastric inflammation severity in WT-infected animals and minimal inflammation in animals infected with mutant strains. Atrophic gastritis (a premalignant condition), dysplasia, and gastric adenocarcinoma were only detected in WT-infected animals with high inflammation scores. Transcriptional profiling, liquid chromatography-tandem mass spectrometry analysis of micro-extracted tryptic peptides, and imaging mass spectrometry revealed more than a thousand molecular alterations in gastric tissues from WT-infected animals with high inflammation scores compared to uninfected tissues and few alterations in tissues from other groups of infected animals. Proteins with altered abundance in animals with severe Cag T4SS-induced inflammation mapped to multiple pathways, including the complement/coagulation cascade and proteasome pathway. Proteins exhibiting markedly increased abundance in tissues from -infected animals with severe inflammation included calprotectin components, proteins involved in proteasome activation, polymeric immunoglobulin receptor (PIGR), interferon-inducible guanylate-binding protein (GBP2), lactoferrin, lysozyme, superoxide dismutase, and eosinophil peroxidase. These results demonstrate key roles for CagA and Cag T4SS activity in promoting gastric mucosal inflammation, transcriptional alterations, and proteomic alterations relevant to gastric carcinogenesis. colonizes the stomachs of about half of humans worldwide, and its presence is the primary risk factor for the development of stomach cancer. strains isolated from humans can be broadly classified into two groups based on whether they contain a chromosomal pathogenicity island, which encodes a secreted effector protein (CagA) and components of a type IV secretion system (T4SS). In experiments using a Mongolian gerbil model, we found that severe gastric inflammation and gastric transcriptional and proteomic alterations related to gastric cancer development were detected only in animals infected with a wild-type strain containing CagA and an intact Cag T4SS Mutant strains lacking CagA or Cag T4SS activity successfully colonized the stomach without inducing detectable pathologic host responses. These findings illustrate two different patterns of -host interaction.