Helicobacter pylori is strongly associated with the majority of duodenal ulcers. The eradication of this organism represents a new approach to treatment of this condition with the potential of reducing or eliminating recurrence. H. pylori is the cause of most cases of type B gastritis. It has also been associated with hypochlorhydria in volunteer studies, in sporadic cases and in small epidemics. Most recently, it has been linked with gastric ulcer and carcinoma. The latter two conditions are often associated with diminished acid secretion. However, despite the potential importance of these associations, very little is known about virulence factors or the pathogenesis of infection by this bacterium. The objectives of this study are an in depth investigation of two factors, that are produced by H. pylori, that inhibit acid secretion from mammalian parietal cells. These factors may be colonizing factors for the bacterium and could explain the temporary hypochlorhydria found early in the natural history of infection. Whether they have a role in explaining the diminished acid secretion often associated with gastric ulcer or carcinoma is unknown. One is a protein and is non-dialysable (AIF-1). The other is a small, heat stable, H+/K+ ionophore (AIF-2). We plan to purify AIF-1 to homogeneity using column chromatography, HPLC and PACE. Once purified we will explore its mechanism of action at the cellular level, in isolated cells and intact gastric mucosa. We propose to further purify AIF-2 and to expand our preliminary observations that have shown that AIF-2 functions by creating ion pores in the parietal cell membrane, thereby eliminating acid secretion. This factor appears to be non-toxic and may represent a novel molecule for controlling acid secretion in man. We plan to examine it s specificity of action on different cells and ions. We will attempt to demonstrate an in vivo response to AIF-1 and AIF-2 with each alone and in combination in the ferret as this a good model of Helicobacter infection and ferret cells are known to respond to AIF-1. Lastly, will use molecular genetic techniques to clone and sequence the gene of AIF-1 as a prelude to defining its regulation. Clinically, AIF-1 and 2 may explain acute hypochlorhydria and be important factors in the hypochlorhydria associated with gastric ulcer and cancer. Their nature an role in the pathogenesis of these disorders requires urgent attention.
| Grubel, P; Hoffman, J S; Chong, F K et al. (1997) Vector potential of houseflies (Musca domestica) for Helicobacter pylori. J Clin Microbiol 35:1300-3 |
| Hoffman, J S; King, W W; Fox, J G et al. (1995) Rabbit and ferret parietal cell inhibition by Helicobacter species. Dig Dis Sci 40:147-52 |
