Stacey N. Harbour

Protease-Activated Receptor-1 Down-regulates the Murine Inflammatory and Humoral Response to Helicobacter pylori

BACKGROUND & AIMS Helicobacter pylori infection results in a diversity of pathologies, from asymptomatic gastritis to adenocarcinoma. The reason for these diverse outcomes is multifactorial and includes host factors that regulate severity of Helicobacter-induced gastritis. Protease-activated receptors (PAR) are environmental sensors that can detect tissue damage and pathogens. Whereas PAR-2 has proinflammatory activity and PAR-1 can protect the gastric mucosa against chemical damage, neither has previously been examined for their potential roles in regulating Helicobacter pathogenesis. METHODS PAR-1(-/-), PAR-2(-/-), and wild-type mice were infected with H pylori for up to 2 months then colonization levels determined by colony-forming assay, gastritis by histology, and serum antibody levels by enzyme-linked immunosorbent assay. Responsiveness of primary epithelial cells to PAR-1 activation was assessed by calcium mobilization assay. Primary epithelial cells, macrophages, and dendritic cells were cocultured with H pylori and nuclear factor (NF)-kappaB, and cytokine secretion was determined by enzyme-linked immunosorbent assay. RESULTS Two months postinfection, H pylori levels were significantly reduced in PAR-1(-/-) and increased in PAR-2(-/-) mice. This effect on colonization was inversely correlated with inflammation severity. Infection of PAR-1(-/-) mice induced an increased serum antibody response. Primary epithelial cells were activated by a PAR-1-activating peptide. H pylori stimulation of primary epithelial cells, but not macrophages or dendritic cells, from PAR-1(-/-) mice induced increased levels of NF-kappaB and the proinflammatory cytokine macrophage-inflammatory protein (MIP)-2. PAR-1 also down-regulated MIP-2 secretion in response to cag pathogenicity island activity. CONCLUSIONS PAR-1 protects the host against severe Helicobacter-induced gastritis. This may be mediated by suppressing the production of proinflammatory cytokines such as MIP-2.

Immunogenicity and pathogenicity of Helicobacter infections of veterinary animals

The initial discovery that the human stomach is commonly infected by the bacterium Helicobacter pylori subsequently resulted in the identification of a whole new family of pathogenic bacteria. In less than 25 years, the Helicobacter genus has grown from obscurity to number at least 38 different species with many more awaiting classifications. These bacteria, many of which are either direct or opportunistic pathogens, are present in virtually every mammalian species examined, and have also now been identified in a number of birds. The pathogenesis associated with these infections is predominantly the result of a chronic inflammatory response mounted by the host against the infection. This is typically a Th1-driven response which can result in a range of conditions from hepatitis, through gallstones to cancer. In some cases the inflammatory response to these infections is normally well managed by the host and disease only results when there is a breakdown or misbalance in the immunoregulatory process, which for example can result in inflammatory bowel disease in experimental models. Understanding the disease association and pathogenic mechanisms of the different Helicobacter infections is clearly of potential significance not only from an animal welfare point of view but also from the growing realisation of how commonly transmission of Helicobacter occurs between different mammals, including pathogenic zoonotic infections of humans.

Localized suppression of inflammation at sites of Helicobacter pylori colonization

ABSTRACT While gastric adenocarcinoma is the most serious consequence of Helicobacter pylori infection, not all infected persons develop this pathology. Individuals most at risk of this cancer are those in whom the bacteria colonize the acid-secreting region of the stomach and subsequently develop severe inflammation in the gastric corpus. It has been reported anecdotally that male mice become infected with greater numbers of H. pylori bacteria than female mice. While investigating this phenomenon, we found that increased H. pylori infection densities in male mice were not related to antibody production, and this phenomenon was not normalized by gonadectomy. However, the gastric pH in male 129/Sv mice was significantly elevated compared with that in female mice. Differences in colonization were evident within 1 day postinfection and significantly arose due to colonization of the gastric corpus region in male mice. This provided a potential model for comparing the effect of corpus colonization on the development of gastritis. This was explored using two models of H. pylori-induced inflammation, namely, 2-month infections of Muc1 −/− mice and 6-month infections of wild-type 129/Sv mice. While H. pylori infection of female mice induced a severe, corpus-predominant atrophic gastritis, to our surprise, male mice developed minimal inflammation despite being colonized with significantly more H. pylori bacteria than female controls. Thus, colonization of the gastric corpus in male mice was associated with a loss of inflammation in that region. The suppression of inflammation concomitant with infection of the gastric corpus in male mice demonstrates a powerful localized suppression of inflammation induced at sites of H. pylori colonization.

Systemic Immunization with Unadjuvanted Whole Helicobacter pylori Protects Mice Against Heterologous Challenge

Background:  Adjuvant‐free vaccines have many benefits, including decreased cost and toxicity. We examined the protective effect of systemic vaccination with adjuvant‐free formalin‐fixed Helicobacter pylori or bacterial lysate and the ability of this vaccine to induce protection against heterologous challenge.

Host Nonresponsiveness Does not Interfere With Vaccine-Mediated Protection Against Gastric Helicobacter Infection

Helicobacter pylori pathogenesis results from the inflammation induced by chronic infection. CBA mice are nonresponsive to gastric Helicobacter infection, providing a useful model for examining host regulation of Helicobacter‐induced gastritis. We examined whether gastric Helicobacter nonresponsiveness impacts upon vaccine efficacy and whether immune‐mediated protection could occur in the absence of inflammation.