Genetic Manipulation of Helicobacter pylori Virulence Function by Host Carcinogenic Phenotypes

Abstract

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 (cagT4SS), which translocates an oncoprotein into host cells. A structural component of the cagT4SS is CagY, which become rapidly altered during in vivo adaptation in mice and rhesus monkeys, rendering the cagT4SS 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 cagT4SS 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 cagT4SS function. The development of dysplasia or cancer selected for attenuated virulence phenotypes, but robust cagT4SS function could be restored upon infection of new hosts. Changes in the genetic composition of cagY mirrored cagT4SS 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 cagT4SS function via altering cagY, allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche.

Pathogenesis of Helicobacter pylori infection

“…During in vivo infection, cag Y sequences may be rapidly altered, resulting in altered activity of cag TFSS, which could be attenuated or similar to the parental strain. Similar findings were observed in the strains isolated from humans . In addition to CagY, the protein structure of CagN and CagM was also characterized.…”

“…17 CagY was reported to play an important role modulating the translocation of CagA and NF-κB and therefore influence inflammation during gerbil infection. 18 During in vivo infection, cagY sequences may be rapidly altered, resulting in altered activity of cag TFSS, which could be attenuated or similar to the parental strain.…”

“…Similar findings were observed in the strains isolated from humans. 18 In addition to CagY, the protein structure of CagN and CagM was also characterized. CagN is reported as a helical and monomeric protein with a molecular weight of 34 kDa measured by the multiangle light scattering (MALS) technique.…”

Pathogenesis of Helicobacter pylori infection

“…Loss of function of the T4SS during in vivo adaptation in mice and primate models is frequent and has been associated with recombination in cag Y. Suarez et al . demonstrated that upon chronic H. pylori infection, cag Y recombination could modulate T4SS function in humans and rodents, which may be important for a successful long‐term persistence of infection.…”

“…Loss of function of the T4SS during in vivo adaptation in mice and primate models is frequent and has been associated with recombination in cagY. Suarez et al 20 demonstrated that upon chronic H. pylori infection, cagY recombination could modulate T4SS function in humans and rodents, which may be important for a successful long-term persistence of infection. The mechanism of cagY alterations was different in human and gerbil isolates, with predominance of single base-pair mutations in human samples and addition/deletion of motifs in the gerbil reisolates.…”