Delineation of the pH-Responsive Regulon Controlled by the Helicobacter pylori ArsRS Two-Component System

Abstract

<i>Helicobacter pylori</i> encounters a wide range of pH within the human stomach. In a comparison of <i>H. pylori</i> cultured <i>in vitro</i> under neutral or acidic conditions, about 15% of genes are differentially expressed, and corresponding changes are detectable for many of the encoded proteins. The ArsRS two-component system (TCS), comprised of the sensor kinase ArsS and its cognate response regulator ArsR, has an important role in mediating pH-responsive changes in <i>H. pylori</i> gene expression. In this study, we sought to delineate the pH-responsive ArsRS regulon and further define the role of ArsR in pH-responsive gene expression. We compared <i>H. pylori</i> strains containing an intact ArsRS system with an <i>arsS</i> null mutant or strains containing site-specific mutations of a conserved aspartate residue (D52) in ArsR, which is phosphorylated in response to signals relayed by the cognate sensor kinase ArsS. We identified 178 genes that were pH-responsive in strains containing an intact ArsRS system but not in Δ<i>arsS</i> or <i>arsR</i> mutants. These constituents of the pH-responsive ArsRS regulon include genes involved in acid acclimatization (<i>ureAB</i>, amidases), oxidative stress responses (<i>katA</i>, <i>sodB</i>), transcriptional regulation related to iron or nickel homeostasis (<i>fur</i>, <i>nikR</i>), and genes encoding outer membrane proteins (including <i>sabA</i>, <i>alpA</i>, <i>alpB</i>, <i>hopD</i> [<i>labA</i>], and <i>horA</i>). When comparing <i>H. pylori</i> strains containing an intact ArsRS TCS with <i>arsRS</i> mutants, each cultured at neutral pH, relatively few genes are differentially expressed. Collectively, these data suggest that ArsRS-mediated gene regulation has an important role in <i>H. pylori</i> adaptation to changing pH conditions.