Genetic Manipulation of <i>Helicobacter pylori</i> Virulence Function by Host Carcinogenic Phenotypes.

Abstract

<i>Helicobacter pylori</i> 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 <i>cag</i> type 4 secretion system (<i>cag</i>T4SS), which translocates an oncoprotein into host cells. A structural component of the <i>cag</i>T4SS is CagY, which becomes rapidly altered during <i>in vivo</i> adaptation in mice and rhesus monkeys, rendering the <i>cag</i>T4SS nonfunctional; however, these models rarely develop gastric cancer. We previously demonstrated that the <i>H. pylori cag</i>⁺ 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 <i>H. pylori</i> to understand how only a subset of infected individuals develop cancer. <i>H. pylori cagY</i> sequence differences and <i>cag</i>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 <i>H. pylori</i> strain 7.13 identified an oscillating pattern of <i>cag</i>T4SS function. The development of dysplasia or cancer selected for attenuated virulence phenotypes, but robust <i>cag</i>T4SS function could be restored upon infection of new hosts. Changes in the genetic composition of <i>cagY</i> mirrored <i>cag</i>T4SS function, although the mechanisms of <i>cagY</i> alterations differed in human isolates (mutations) versus gerbil isolates (addition/deletion of motifs). These results indicate that host carcinogenic phenotypes modify <i>cag</i>T4SS function via altering <i>cagY,</i> allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche. <i>Cancer Res; 77(9); 2401-12. ©2017 AACR</i>.