Detailed In Vivo Analysis of the Role of Helicobacter pylori Fur in Colonization and Disease

Abstract

ABSTRACT Helicobacter pylori persistently colonizes the harsh and dynamic environment of the stomach in over one-half of the world's population and has been identified as a causal agent in a spectrum of pathologies that range from gastritis to invasive adenocarcinoma. The ferric uptake regulator (Fur) is one of the few regulatory proteins that has been identified in H. pylori . Fur regulates genes important for acid acclimation and oxidative stress and has been shown to be important for colonization of H. pylori in both murine and Mongolian gerbil models of infection. To more thoroughly define the role of Fur in vivo , we conducted an extensive temporal analysis of the location of, competitive ability of, and resultant pathology induced by a Δ fur strain in the Mongolian gerbil model of infection and compared the results to results for its wild-type parent. We found that at the earliest time points postinfection, significantly more Δ fur bacteria than wild-type bacteria were recovered. However, this trend was reversed by day 3, when there was significantly increased recovery of the wild-type strain. The increased recovery of the Δ fur strain at 1 day postinfection reflected increased recovery from both the corpus and the antrum of the stomach. When the wild-type strain was allowed to colonize first, the Δ fur strain was unable to compete for colonization at any time postinfection. However, when the Δ fur strain was allowed to colonize first, the wild type efficiently outcompeted the Δ fur strain only at early times postinfection. Finally, we demonstrated that there was a delay in the development and severity of inflammation and pathology of the Δ fur strain in the gastric mucosa even after comparable levels of colonization occurred. Together, these data indicate that H. pylori Fur is most important at early stages of infection and illustrate the importance of the ability of H. pylori to adapt to its constantly fluctuating environment when it is establishing infection, inflammation, and disease.