Role of Helicobacter Pylori in the Pathogenesis of Childhood Asthma

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DESCRIPTION (provided by applicant): Helicobacter pylori commonly infects the human stomach, where it causes inflammation (gastritis) in all individuals and peptic ulcer disease or gastric cancer in some. The prevalence of H. pylori in children in developed countries is less than 10%, while it is nearly universal in most developing countries. As the prevalence of H. pylori has declined, several diseases have dramatically increased, one of which is childhood asthma. Recent retrospective and case control studies suggest that infection with H. pylori, particularly strains bearing the proinflammatory cag pathogenicity island, is inversely associated with asthma. H. pylori induction of a regulatory T cell (Treg) response in children is a biologically plausible mechanism that may explain this association. The primary objective of this proposal is to determine if early life exposure to H. pylori can prevent the development of childhood asthma. Our overall hypothesis is that H. pylori promotes a Treg-biased immune response in children that can suppress synthesis of pulmonary and systemic cytokines that promote allergic inflammation, thereby protecting the airways from development of reactivity in early life. This hypothesis is based on our preliminary findings in rhesus macaques that Treg cells in maturing airways are attenuated by house dust mite aerosol exposure, and the published observation that H. pylori promotes development of gastric mucosal Treg cells in children. Thus, we propose that enhancement of Treg cell populations by H. pylori infection may prevent the inhibitory effects of aeroallergen on this immunosuppressive lymphocyte. The rhesus macaque models of H. pylori and asthma developed at the California National Primate Research Center (CNPRC) provide a unique opportunity to study the hypothesis that H. pylori protects against childhood asthma, which we will test with the following specific aims: (1) Determine if experimental H. pylori infection can prevent the asthma phenotype in the infant rhesus macaque model of childhood asthma. (2) Examine the effects of H. pylori infection on systemic, gastric, and pulmonary immune correlates of the childhood asthma phenotype. Completion of these Specific Aims will provide important experimental support for epidemiologic findings, and may be directly extrapolated towards identification of candidate compounds for the prevention of childhood asthma and other co-morbid conditions.