Helicobacter pylori induces a novel form of innate immune memory via accumulation of NF-кB proteins, 2023, Frauenlob et al.

[SNT Gatchaman]

Helicobacter pylori induces a novel form of innate immune memory via accumulation of NF-кB proteins
Frauenlob, Tobias; Neuper, Theresa; Regl, Christof; Schaepertoens, Veronika; Unger, Michael S.; Oswald, Anna-Lena; Dang, Hieu-Hoa; Huber, Christian G.; Aberger, Fritz; Wessler, Silja; Horejs-Hoeck, Jutta

Helicobacter pylori is a widespread Gram-negative pathogen involved in a variety of gastrointestinal diseases, including gastritis, ulceration, mucosa-associated lymphoid tissue (MALT) lymphoma and gastric cancer. Immune responses aimed at eradication of H. pylori often prove futile, and paradoxically play a crucial role in the degeneration of epithelial integrity and disease progression. We have previously shown that H. pylori infection of primary human monocytes increases their potential to respond to subsequent bacterial stimuli – a process that may be involved in the generation of exaggerated, yet ineffective immune responses directed against the pathogen.

In this study, we show that H. pylori-induced monocyte priming is not a common feature of Gram-negative bacteria, as Acinetobacter lwoffii induces tolerance to subsequent Escherichia coli lipopolysaccharide (LPS) challenge. Although the increased reactivity of H. pylori-infected monocytes seems to be specific to H. pylori, it appears to be independent of its virulence factors Cag pathogenicity island (CagPAI), cytotoxin associated gene A (CagA), vacuolating toxin A (VacA) and γ-glutamyl transferase (γ-GT).

Utilizing whole-cell proteomics complemented with biochemical signaling studies, we show that H. pylori infection of monocytes induces a unique proteomic signature compared to other pro-inflammatory priming stimuli, namely LPS and the pathobiont A. lwoffii. Contrary to these tolerance-inducing stimuli, H. pylori priming leads to accumulation of NF-кB proteins, including p65/RelA, and thus to the acquisition of a monocyte phenotype more responsive to subsequent LPS challenge.

The plasticity of pro-inflammatory responses based on abundance and availability of intracellular signaling molecules may be a heretofore underappreciated form of regulating innate immune memory as well as a novel facet of the pathobiology induced by H. pylori.

Link | PDF (Frontiers in Immunology)

 

[SNT Gatchaman]

We previously described the startling observation that infection of primary human monocytes with H. pylori, rather than inducing immediate tolerance, promotes responsiveness to subsequent LPS challenge. Here we report that the hyperresponsiveness to LPS challenge after H. pylori priming is not a general adaptation elicited by Gram-negative bacteria, as A. lwoffii infection of monocytes results in robust tolerance to a subsequent stimulus.

Notably, the NRF2 and NF-кB signaling pathways and their constituent proteins seem to be significantly upregulated in H. pylori-primed monocytes in comparison to LPSand A. lwoffii-primed cells.

Until recently it was thought that phenomena such as endotoxin tolerance and trained immunity predominantly depend on metabolic reprogramming and epigenetic regulation of proinflammatory gene promoter accessibility to induce transient silencing (or long-lasting “priming”) of these genes. New insights have led to the postulation that fluctuations in abundance of intracellular signaling proteins may represent an additional form of acute innate immune memory. Wang and colleagues demonstrated, in models of acute memory formation, that dynamic remodeling of the NF-кB signaling network reflecting prior stimulation has profound effects on a cell’s capacity to respond to subsequent stimulation.

Intriguingly, it has recently been shown that NF-кB dynamics and oscillations in turn influence epigenomic reprogramming of macrophages in response to different stimuli, highlighting the interconnectedness of different forms of acute and long-term innate immune memory.

 

[SNT Gatchaman]

Our analysis describes opposite forms of innate immune memory, both potentiating and negating subsequent immune responses: H. pylori-primed monocytes show enhanced functional NF-кB signaling, whereas LPS- and A. lwoffii-tolerized cells effectively shut down the pathway. The resulting overactivation of H. pylori-primed monocytes leads to increased cytokine responses to subsequent LPS challenge. This hyperactivity could contribute to gastric pathology and inflammation in the context of H. pylori infection.

The spike in innate immune cell reactivity after contact with the pathogen could also concurrently contribute to the disappearance of other bacterial species from the gastric compartment in presence of the H. pylori: several reports have shown dramatic gastric microbiota composition changes upon infection with H. pylori, as the microbial diversity of the stomach severely decreases in H. pylori-positive individuals.

Intriguingly, Ferreira and colleagues reported that dysbiosis and loss of microbial richness was even more pronounced in gastric carcinoma samples, albeit the relative abundance of H. pylori decreased, implying that the damage may have been done. These findings indicate that the degradation of the microbiota composition may play a pivotal role in the etiology of gastric carcinomas.

 

[SNT Gatchaman]

But remember kids: stomach ulcers and cancer are psychogenic and caused by life stress.