Vacuolating Cytotoxin of Helicobacter pylori Plays a Role during Colonization in a Mouse Model of Infection

Vacuolating Cytotoxin of Helicobacter pylori Plays a Role during Colonization in a Mouse Model of Infection,10.1128/IAI.69.2.730-736.2001,Infection an

Vacuolating Cytotoxin of Helicobacter pylori Plays a Role during Colonization in a Mouse Model of Infection   (Citations: 89)
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Helicobacter pylori, the causative agent of gastritis and ulcer disease in humans, secretes a toxin called VacA (vacuolating cytotoxin) into culture supernatants. VacA was initially characterized and purified on the basis of its ability to induce the formation of intracellular vacuoles in tissue culture cells. H. pylori strains possessing different alleles of vacA differ in their ability to express active toxin. Those strains expressing higher toxin levels are correlated with more severe gastric disease. However, the specific role(s) played by VacA during the course of infection and disease is not clear. We have used a mouse model of H. pylori infection to begin to address this role. A null mutation of vacA compromises H. pylori in its ability to initially establish infection. If an infection by a vacA mutant is established, the bacterial load and degree of inflammation are similar to those associated with an isogenic wild-type strain. Thus, in this infection model, vacA plays a role in the initial colonization of the host, suggesting that strains of H. pylori expressing active alleles of vacA may be better adapted for host-to-host transmission. Helicobacter pylori infection of the human stomach can result in a broad spectrum of disease outcomes ranging from mild gastritis to severe ulcers (8). Additionally, H. pylori is associ- ated with two types of cancer: gastric lymphoid tissue-associ- ated B-cell lymphoma (32, 34) and gastric adenocarcinoma (25). The disease outcome in each infected individual appears to be determined by a combination of host and bacterial fac- tors. The genotypes of H. pylori clinical isolates vary in many genetic loci, including the presence or absence of a pathoge- nicity island (1, 5) and allelic variation of the vacuolating cy- totoxin gene (vacA) (2) and genes encoding adhesion mole- cules such as BabA2, which binds the Lewis b fucosylated moiety found on human gastric tissue (16). Epidemiological studies suggest that strains expressing the pathogenicity island, those expressing high levels of VacA, and those expressing functional BabA2 correlate with more severe disease (8, 13). VacA enters eukaryotic cells and exerts its action in the cytoplasm (9, 12). VacA recently was shown to form chloride- conducting channels in both artificial and cellular lipid bilayers (30). Additionally, cells exposed to VacA accumulate vesicles containing rab7, a cellular marker of the late endosome, and lgp110, a marker of lysosomes (21, 24). This VacA-induced alteration of intracellular membranes has been shown to dis- rupt normal lysosomal degradation of surface receptors in ep- ithelial cells (28) and to interrupt antigen processing in im- mune cells (22). Comparison of vacA gene sequences among clinical isolates has revealed variability both in the coding region of the signal sequence and in the middle region of the functional protein. Certain alleles of the signal sequence cor- relate both with higher expression of active toxin and with more severe disease (2). Alleles of the middle region probably act in targeting and internalization of the toxin but do not affect toxin activity once it enters the host cell cytoplasm (23). The mechanisms by which VacA contributes to infection and disease have remained elusive. Vacuolization of cells in human biopsy samples has been observed (4, 11), and oral adminis- tration of partially purified toxin to mice was shown to cause measurable epithelial damage (14). However, isogenic vacA mutants not only colonize but also cause indistinguishable de- grees of gastritis in both gnotobiotic piglets (10) and Mongo- lian gerbils (33). These results, suggesting that vacA is not a virulence factor, contradict the human epidemiology data. This may reflect differences in the animal models relative to the human host or may indicate that VacA is not essential for the establishment or persistence of H. pylori infection. The latter conclusion is particularly unsatisfying since the presence of vacA seems to distinguish H. pylori from Helicobacter species that do not infect humans or interact intimately with the gastric epithelium in their natural hosts (19). We decided to reexamine the role of VacA in an established mouse model of infection using H. pylori strain SS1 in C57BL/ 6NTac mice (20). In this model system, we found that isogenic vacA null mutants are severely defective in the ability to es- tablish initial colonization of the host, which profoundly atten- uates the virulence potential of these strains.
Journal: Infection and Immunity - INFEC IMMUNITY , vol. 69, no. 2, pp. 730-736, 2001
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