Two-Component Systems of Helicobacter pylori Contribute to Virulence in a Mouse Infection Model

Abstract

Helicobacter pylori encodes three histidine kinases and five response regulators belonging to the family of two-component regulatory systems which are involved in transcriptional control. Here we demonstrate that isogenic mutants of H. pylori P76 with deletions of the response regulator open reading frame (ORF) HP1365 and ORFs HP244, HP165, and HP1364 encoding histidine kinases are unable to colonize the stomachs of BALB/c mice, suggesting an essential role of these systems in the regulation of important virulence properties of H. pylori. Furthermore, we demonstrate that the genes under the control of the P HP1408 and P HP119 promoters which are regulated by the two-component system HP166-HP165 are not essential for single mutant colonization of mice but are required under competitive colonization conditions.

Structural Analysis of the DNA-binding Domain of the Helicobacter pylori Response Regulator ArsR

“…Protein samples estimated to be Ͼ95% pure were analyzed by NMR. 15 N-and 13 C, 15 N-labeled samples were produced by a process similar to that described above, but cells were grown in M9 medium with the addition of 13 C-labeled glucose and 15 Nlabeled ammonium chloride (CIL, Andover, MA).…”

“…Gel-shift and DNA-footprinting analyses have shown that ArsR binds directly to the promoter regions of these genes (17,18). Thus, the ArsRS TCS has an important role in allowing H. pylori to regulate gene expression in response to changes in pH and also has an important role in allowing H. pylori to colonize the gastric mucosa (15).…”

“…Evidence supporting a cognate relationship between ArsS and ArsR includes immediate proximity of the two genes in the H. pylori chromosome and the demonstration that the two purified proteins can participate in a phosphotransfer reaction in vitro (12). H. pylori ArsS null mutants are viable, but such mutants are impaired in the ability to grow in low pH in vitro, and these mutant strains are unable to colonize mice (14,15). Attempts to generate ArsR null mutants have been unsuccessful, which suggests that ArsR is essential for H. pylori viability (12).…”

“…Several recent studies reported that an H. pylori TCS, ArsSArsR (acid-responsive signaling sensor/response regulator), responds to acidic conditions (12)(13)(14)(15)(16)(17)(18)(19)(20). This TCS consists of the histidine kinase protein, ArsS, and the RR protein, ArsR.…”

“…Therefore, H. pylori has evolved mechanisms to survive severe acid shock and grow under moderately acidic conditions. One of the important mechanisms by which H. pylori responds to acidic pH involves regulation of gene expression through a two-component signal transduction system (12)(13)(14)(15)(16)(17)(18)(19)(20).…”