Immune Responses of Specific-Pathogen-Free Mice to Chronic Helicobacter pylori (Strain SS1) Infection

A model permitting the establishment of persistent Helicobacter pylori infection in mice was recently described. To evaluate murine immune responses to H. pylori infection, specific-pathogen-free Swiss mice (n = 50) were intragastrically inoculated with 1.2 × 10⁷ CFU of a mouse-adapted H. pylori isolate (strain SS1). Control animals (n = 10) received sterile broth medium alone. Animals were sacrificed at various times, from 3 days to 16 weeks postinoculation (p.i.). Quantitative culture of gastric tissue samples from inoculated mice demonstrated bacterial loads of 4.0 × 10⁴ to 8 × 10⁶ CFU per g of tissue in the animals. Infected mice had H. pylori-specific immunoglobulin M (IgM) and IgG antibodies in serum (at day 3 p.i.) and IgG and IgA antibodies in their gastric contents (weeks 4 and 16 p.i.) and saliva (week 16 p.i.). Mucosal IgM antibodies were not detected. Histological examination of the gastric mucosae from control and infected mice revealed mild chronic gastritis, characterized by the presence of polymorphoneutrophil cell infiltrates and submucosal lymphoid aggregates, in infected animals at 16 weeks p.i. Differences in the quantities of IgG1 and IgG2a subclass antibodies detected in the sera of mouse strains (Swiss, BALB/c, and C57BL/6) infected by H. pylori suggested that host factors influence the immune responses induced against this bacterium in the host. In conclusion, immune responses to H. pylori infection in mice, like those in chronically infected humans, appear to be ineffective in resolving the infection.The presence of Helicobacter pylori bacteria in human gastric mucosae induces marked immune responses in the host (for a review, see reference 10). Volunteer ingestion experiments and case reports have shown that individuals develop severe polymorphonuclear leukocyte inflammation of the stomach mucosa soon after infection by H. pylori (23, 29). In addition, acutely infected individuals were reported to have anti-H. pylori immunoglobulin A (IgA) and IgM class antibodies in their gastric juice and/or sera within several weeks after having been infected (26, 27, 33). Though there has been some evidence of spontaneous eradication of H. pylori by the host (2, 26), most untreated individuals remain infected with the organism. In such cases, subjects develop a chronic gastritis which is characterized by the formation of gastric lymphoid tissue (10).Various animal models have been developed for study of H. pylori pathogenesis, and, until recently, those using large animal hosts such as gnotobiotic piglets, nonhuman primates, and cats have been the most successful at reproducing the pathology associated with human infection (for a review, see reference 14). Nevertheless, such models are relatively cumbersome and have a restricted applicability because of difficulties in handling large numbers of infected animals for significant periods and because of the limited availability of immunological reagents for these host species.In 1991, Karita and colleagues (18) established transient H. pylori infections in immunodeficient BALB/c animals, thus demonstrating for the first time that it was possible to colonize a small laboratory animal with H. pylori. More recently, there have been reports of the colonization of immunocompetent mice with mouse-adapted H. pylori isolates (19, 22, 24). By screening various H. pylori clinical isolates for their capacity to colonize mice, Lee and colleagues (21) identified one H. pylori strain (named SS1, or the Sydney strain) that, after adaptation to mice, was able to colonize mouse gastric mucosae in high numbers and for long periods (≤8 months).Data on host immune responses to H. pylori in humans have, for the most part, arisen from investigations of chronically infected individuals (2, 5, 6, 31), while studies with animal models have tended to focus on responses associated with acute or short-term H. pylori infections (18, 19, 22, 24). In this study, we sought to evaluate host immune responses to H. pylori in a murine infection model. To this end, mice were infected with H. pylori SS1 and the humoral immune responses of the animals were assessed over time. The findings demonstrated that chronic H. pylori SS1 infection in mice induced humoral immune responses that closely mimicked those observed in human H. pylori infections. As has been found to be the case for infected humans, adaptive immune responses do not appear to be effective in eradicating an existent H. pylori infection in mice. This is the first report detailing the humoral responses of mice to a persistent H. pylori infection.