Inhibition of Treg function to cure persistent H. pylori infection

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DESCRIPTION (provided by applicant): Over half of the world's population is infected with Helicobacter pylori. It is well known that individuals usually get infected in childhood and the infection persists for life. It is the persistence of this infection that leads to the sequence of events that cause gastritis, gastroduodenal ulceration, gastric cancer and lymphoma. Studies of the epidemiology of H. pylori have failed to identify an intervention that would prevent infection reliably, particularly of the poor. Antibiotic treatment is only recommended for the prevention of recurrent ulcers and as an adjunctive therapy for infected patients with early stage gastric maltomas. To date, vaccination has not been developed successfully. Thus, in the absence of effective approaches to prevent or cure this persistent infection, novel interventional strategies are required to avoid the clinical consequences of chronic inflammation induced by this persistent infection. Regulatory T cells (Treg) have been identified as important factors in favoring persistent infection. During infection with H. pylori, Treg are increased in human and murine gastric tissue. Further, depopulating Treg allows the local host responses to intensify and infection is decreased. We have identified that extracellular adenosine, a mediator produced by Treg, plays a major role in sustaining the persistent infection to H. pylori. Our long term goal is to develop a therapeutic strategy to easily and safely boost host immunity to clear infection. The rationale for the proposed research is that new knowledge of the mechanisms that favor persistent infection will expose points that can be targeted for intervention. This lead to our current hypothesis that blocking the action of adenosine will enhance immunity and favor the clearance of persistent H. pylori infection. The broad objectives for the proposed studies are to evaluate the effects of blocking adenosine production or action on H. pylori infection and test a family of compounds for their ability to prevent persistent infection with this organism. This objective will be addressed in the following Specific Aims: Aim 1: Evaluate the effect of blocking adenosine production/action on persistent H. pylori infection. Aim 2: Optimize the efficacy of blocking adenosine to enhance anti-bacterial immunity. Aim 3: Support the rationale for drug development using human tissue and non-human primates. Together, these studies will advance the development of therapeutic approaches targeting mediators of Treg function that attenuate host responses and favor persistent infection with H. pylori. This new information will have an important positive impact by advancing our understanding of the mechanisms regulating persistence and serve as the basis for new therapeutic strategies that enhance host responses to clear these infections.