Helicobacter pylori priming of human monocytes induces hyperresponsive activation state via accumulation of NF-кB proteins

Description

The gram-negative pathogen Helicobacter pylori infects approximately 50 % of the world’s human population and represents a significant risk factor for gastric ulcer and stomach cancer development. Due to successful co-evolution with its host and development of unique adaptive strategies, H. pylori infection leads to persistent colonization of the gastric mucosa and to chronic inflammation. Immune cells infiltrating the inflamed epithelium contribute significantly to the degeneration and atrophy of the stomach lining. Various scientific advances have shown that H. pylori infection has profound effects on peripheral adaptive immune memory responses. The formation of innate immune memory in response to H. pylori and its influence on innate immune function, on the other hand, has only been sparsely investigated. While other bacterial stimuli commonly induce tolerance in priming and challenge models, H. pylori priming seems to not only maintain, but promote the responsiveness of monocytes to E. coli LPS. Utilizing whole-cell proteomics complemented with biochemical signaling studies, we compare innate immune memory formation to various pro-inflammatory stimuli, including gram-negative pathogens H. pylori and Acinetobacter lwoffii. In agreement with previous findings, we observed increased responsiveness to LPS after H. pylori priming – an effect independent on expression of major virulence factors, while tolerance was induced by A. lwoffii. Further we identified significant H. pylori-specific upregulation of NF-кB transcription factor family members. Accordingly, we showed that functional signaling via the NF-кB pathway is not only retained but enhanced after H. pylori priming, while being shut down by other priming stimuli. Lastly, we elucidated that the monocyte hyperresponsiveness induced by H. pylori is indeed dependent on NF-кB activity, as it can be abrogated by inhibiting IKKαβ kinase, an essential enzyme involved in NF-кB signal transduction. Taken together, these findings illustrate that H. pylori infection induces a hyperresponsive activation state in human primary monocytes via amplified NF-кB signaling. Thereby, increased reactivity to subsequent ubiquitous bacterial stimuli (such as LPS) leads to overproduction of inflammatory mediators. The resulting exacerbation of inflammatory processes coupled with consequent insults to epithelial integrity by H. pylori provides fertile soil for and could contribute to the development of gastric malignancies.

Period	19 Sept 2023 → 21 Sept 2023
Event title	15th ÖGMBT Annual Meeting: Life Sciences and cutting-edge technologies
Event type	Conference
Location	Salzburg, AustriaShow on map
Degree of Recognition	International