Direct sensing of host ferric iron by an archetype histidine kinase mediates virulence of an enteric pathogen

作者：Yibei Zhang, Gang Xiao, Haoyuan Ding, Qian Zou, Dan Gu, Jiachen Wen, Yonggang Pei, Rongxian Guo, Qiyao Wang, Xiaohui Zhou · 发表于：Proceedings of the National Academy of Sciences · 年份：2025 · DOI：10.1073/pnas.2507874122 · 被引用次数：13 · 研究领域：Vibrio bacteria research studies、Escherichia coli research studies、Bacterial Genetics and Biotechnology

Two-component system (TCS) histidine kinases enable bacterial pathogens to sense environmental signals and regulate adaptive responses during infection. The EnvZ/OmpR TCS, known for its role in osmolarity/pH-dependent regulation of outer membrane porins across bacterial species, is also a central virulence regulator. However, the environmental cues that activate EnvZ/OmpR to trigger pathogenicity have remained unclear, limiting our understanding of host–pathogen interactions. Here, we demonstrate that in Vibrio parahaemolyticus , a major etiological agent of seafood-associated gastroenteritis, EnvZ functions as a direct ferric iron (Fe 3+ ) sensor governing virulence programs. Fe 3+ -EnvZ interaction triggers kinase phosphorylation and activation, enabling transcriptional control of biofilm formation, swarming motility, and type 3/6 secretion systems. An iron-binding-deficient EnvZ mutant (EnvZ Q103A ) abrogated Fe 3+ responsiveness and downstream signaling pathways. In an infant rabbit infection model, Fe 3+ enhanced V. parahaemolyticus intestinal colonization and virulence through EnvZ/OmpR signaling. This study identifies Fe 3+ as the physiological ligand activating the EnvZ/OmpR virulence regulon and provides insight into how enteric pathogens exploit host-derived iron cues to promote infection.