Regulatory Networks in Helicobacter pylori: The Roles of Two-Component Systems and CsrA in Stress Adaptation

Helicobacter pylori (H. pylori) is a major human pathogen, infecting nearly half of the global population. It has evolved remarkable adaptability to the harsh gastric environment, contributing to gastrointestinal diseases and gastric cancer. During infection, H. pylori encounters various environmental stresses, including acidity, reactive species, metal ion fluctuations, and osmotic changes. Two-component systems (TCSs) are key regulatory mechanisms that enable bacteria to respond to such environmental stimuli. Compared to other gram-negative bacteria, H. pylori encodes a relatively limited number of TCSs, consisting of four (ArsRS, CrdRS, FlgRS, and CheY1Y2A) along with two orphan regulators (HP1021 and HsrA). These systems regulate gene transcription, playing essential roles in bacterial adaptation and survival. Additionally, the global regulator CsrA, positioned at the center of the regulatory hierarchy, orchestrates stress response mechanisms. This review summarizes how H. pylori utilizes TCSs and CsrA to modulate cellular responses under environmental stresses. We further explore potential interactions among these regulators and discuss the feasibility of targeting TCSs and CsrA as alternative strategies for H. pylori treatment.