Abstract
The gastric pathogen Helicobacter pylori requires a noncanonical cytosolic chemoreceptor transducer-like protein D (TlpD) for efficient colonization of the mammalian stomach. Here, we reconstituted a complete chemotransduction signaling complex in vitro with TlpD and the chemotaxis (Che) proteins CheW and CheA, enabling quantitative assays for potential chemotaxis ligands. We found that TlpD is selectively sensitive at micromolar concentrations to bleach (hypochlorous acid, HOCl), a potent antimicrobial produced by neutrophil myeloperoxidase during inflammation. HOCl acts as a chemoattractant by reversibly oxidizing a conserved cysteine within a 3His/1Cys Zn-binding motif in TlpD that inactivates the chemotransduction signaling complex. We found that H. pylori is resistant to killing by millimolar concentrations of HOCl and responds to HOCl in the micromolar range by increasing its smooth-swimming behavior, leading to chemoattraction to HOCl sources. We show related protein domains from Salmonella enterica and Escherichia coli possess similar reactivity toward HOCl. We propose that this family of proteins enables host-associated bacteria to sense sites of tissue inflammation, a strategy that H. pylori uses to aid in colonizing and persisting in inflamed gastric tissue.
Highlights
Helicobacter pylori is a bacterial pathogen and persistent colonizer of the human stomach and can cause gastritis, ulcers, and stomach cancer [1]
We show that in vitro the strong oxidant hypochlorous acid (HOCl, bleach), the major oxidative product generated by neutrophilic inflammation, potently and reversibly inactivates the signaling complex through a universally conserved cysteine in the transducer-like protein D (TlpD) chemoreceptor zinc-binding (CZB) to elicit a chemoattractant signaling response, and that reactivity toward HOCl is a conserved feature of CZB domains from other bacteria
H. pylori TlpD is unusual for a chemoreceptor, because it contains an abundance of Cys residues (4–5 depending on the strain): C35, C103, C117, C308, and C340 (Fig 1D)
Summary
Helicobacter pylori is a bacterial pathogen and persistent colonizer of the human stomach and can cause gastritis, ulcers, and stomach cancer [1]. The health burden caused by H. pylori is large because it infects about half the world’s population, with nearly 100% infection rates in some developing regions, and drug resistance to first-line antibiotics is increasing [1,2]. Despite triggering a robust inflammation response and bursts of reactive oxygen species (ROS) from immune cells, H. pylori avoids clearance and persists for many decades [3]. The chronic inflammation induced by H. pylori infection is thought to be a major factor in causing. A bacterial pathogen is attracted to bleach. Role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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