Helicobacter pylori induces a novel form of innate immune memory via accumulation of NF-кB proteins

Abstract

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.

Trained Immunity and Trained Tolerance: The Case of Helicobacter pylori Infection

“…When primary human monocytes are infected with H. pylori , the TI mechanisms elicit hyperresponsiveness to subsequent LPS challenges [ 44 ]. It has also been demonstrated that monocyte priming by H. pylori induces innate immune memory characterized by intense nuclear translocation of NF-κB proteins, which elicits a vigorous response to the persistence of infection [ 45 ]. LPS priming induces methylation at H3K4 in macrophages [ 46 ], as well as increased phosphorylation of transcription factors, such as ATF7 [ 47 ], resulting in a stable decrease of repressive H3K9me2.…”

Bioactive peptides as alternative treatment for Helicobacter pylori infection

“…As previously noted, the majority of patients infected with H. pylori exhibit histologic gastritis, and the phenotype of this gastritis will influence the progression of symptoms [48][49][50]. Most of the patients have a mild gastritis phenotype that in general is asymptomatic and do not affect the acid secretion, 10 to 15% presents the duodenal ulcer phenotype that affects the secretory function with a higher production of gastrin and acid secretion, with disturbances in the inhibitory control of acid secretion leading to dyspeptic symptoms and/or duodenal ulcer, and less than 1% present the gastric cancer phenotype that culminates in a strong reduction or absence of acid secretion, leading to severe atrophic gastritis, intestinal metaplasia and gastric cancer [21,34,[51][52][53]. In Figure 2 the treatment and strain genetic mutations have been determined and described in literature [58,59].…”