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Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma, yet only a minority of infected persons ever develop this malignancy. One cancer-linked locus is the cag type 4 secretion system ( cag T4SS), which translocates an oncoprotein into host cells. A structural component of the cag T4SS is CagY, which becomes rapidly altered during in vivo adaptation in mice and rhesus monkeys, rendering the cag T4SS nonfunctional; however, these models rarely develop gastric cancer. We previously demonstrated that the H. pylori cag  + strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. We now use this model, in conjunction with samples from patients with premalignant lesions, to define the effects of a carcinogenic host environment on the virulence phenotype of H. pylori to understand how only a subset of infected individuals develop cancer. H. pylori cagY sequence differences and cag T4SS function were directly related to the severity of inflammation in human gastric mucosa in either a synchronous or metachronous manner. Serial infections of Mongolian gerbils with H. pylori strain 7.13 identified an oscillating pattern of cag T4SS function. The development of dysplasia or cancer selected for attenuated virulence phenotypes, but robust cag T4SS function could be restored upon infection of new hosts. Changes in the genetic composition of cagY mirrored cag T4SS function, although the mechanisms of cagY alterations differed in human isolates (mutations) versus gerbil isolates (addition/deletion of motifs). These results indicate that host carcinogenic phenotypes modify cag T4SS function via altering cagY, allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche. Cancer Res; 77(9); 2401-12. ©2017 AACR .

Genetic Manipulation of Helicobacter pylori Virulence Function by Host Carcinogenic Phenotypes