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Published on: January 7, 2020
Helicobacter pylori PldA modulates TNFR1-mediated p38 signaling pathways to regulate macrophage responses for its
Wei Yang Sit1, Mei-Ling Cheng2, Tsan-Jan Chen1
1Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan, ROC.
Abstract:
Helicobacter pylori, a dominant member of the gastric microbiota was associated with various gastrointestinal diseases and presents a significant challenge due to increasing antibiotic resistance. This study identifies H. pylori's phospholipase A (PldA) as a critical factor in modulating host macrophage responses, facilitating H. pylori 's evasion of the immune system and persistence. PldA alters membrane lipids through reversible acylation and deacylation, affecting their structure and function. We found that PldA incorporates lysophosphatidylethanolamine into macrophage membranes, disrupting their bilayer structure and impairing TNFR1-mediated p38-MK2 signaling. This disruption results in reduced macrophage autophagy and elevated RIP1-dependent apoptosis, thereby enhancing H. pylori survival, a mechanism also observed in multidrug-resistant strains. Pharmacological inhibition of PldA significantly decreases H. pylori viability and increases macrophage survival. In vivo studies corroborate PldA's essential role in H. pylori persistence and immune cell recruitment. Our findings position PldA as a pivotal element in H. pylori pathogenesis through TNFR1-mediated membrane modulation, offering a promising therapeutic target to counteract bacterial resistance.
Insights
Helicobacter pylori phospholipase A (PldA) disrupts macrophage immune responses, aiding bacterial survival and antibiotic resistance. Inhibiting PldA offers a promising therapeutic strategy against H. pylori infections.
Area of Science:
- Microbiology
- Immunology
- Molecular Biology
Background:
- Helicobacter pylori is a major cause of gastrointestinal diseases.
- Increasing antibiotic resistance in H. pylori poses a significant clinical challenge.
Purpose of the Study:
- To investigate the role of H. pylori phospholipase A (PldA) in host immune modulation.
- To identify PldA as a potential therapeutic target against H. pylori.
Main Methods:
- Studied the effect of PldA on macrophage membrane lipids and signaling pathways.
- Assessed the impact of PldA inhibition on H. pylori viability and host cell survival.
- Conducted in vivo studies to evaluate PldA's role in bacterial persistence and immune response.
Main Results:
- PldA incorporates lysophosphatidylethanolamine into macrophage membranes, disrupting bilayer structure.
- PldA impairs TNFR1-mediated p38-MK2 signaling, reducing autophagy and increasing apoptosis in macrophages.
- Pharmacological inhibition of PldA reduced H. pylori viability and enhanced macrophage survival.
- In vivo studies confirmed PldA's essential role in H. pylori persistence and immune cell recruitment.
Conclusions:
- H. pylori PldA is critical for immune evasion by modulating host macrophage membranes via TNFR1 signaling.
- PldA is a key virulence factor and a promising therapeutic target for combating H. pylori infections, including multidrug-resistant strains.
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