Effects of ADP-heptose on human primary dendritic cells

Description

The Gram-negative bacterium Helicobacter pylori is perfectly adapted to the gastric environment and infection leads to persistent colonization of the gastric mucosa. Immune cells infiltrating the epithelial layer cause chronic inflammation and contribute significantly to the deterioration and atrophy of the epithelial lining. Among the numerous infiltrating immune cells, dendritic cells (DCs) are essential for maintaining the delicate balance between stimulating potent inflammatory reactions and inducing tolerance, as they instruct immediate innate responses as well as effectively prime T cell responses. The recognition of conserved pathogen-associated molecular patterns (PAMPs) by DCs is an essential feature of the innate immune system enabling the initiation of a rapid antimicrobial immune response. Recent scientific advances have identified metabolic intermediates of the lipopolysaccharide (LPS) biosynthesis pathway as novel PAMPs of Gram-negative bacteria, with ADP-heptose being the most potent. While most studies attributing PAMP status to ADP-heptose relied on epithelial cell models, this study aims to extend our understanding of the role of ADP-heptose beyond the epithelial barrier. Therefore, we are investigating the capacity of the recently described PAMP to activate human DCs using H. pylori infection as a model system. Utilizing an ADP-heptose devoid H. pylori mutant, co-culture systems, spatial biology, whole cell proteomics, flow cytometry and biochemical methods, we carefully monitor DC and T cell activation as well as intracellular signaling cascades to determine the contribution of ADP-heptose to pro-inflammatory processes induced by H. pylori. We show that DCs are significantly enriched in gastric biopsies of H. pylori positive gastritis patients. Moreover, to further emphasize the importance of DCs in the context of H. pylori infection, we demonstrate that DCs cultured in a mucosoid/DC co-culture are activated upon infection of the mucosoid. Additionally, we found that ADP-heptose modulates the activation status of human DCs in the context of an H. pylori infection. Innate immune signaling pathways are regulated by ADP-heptose thereby affecting the H. pylori-induced DC phenotype as well as the subsequent T cell response. Thus, we can conclude that in the context of a bacterial infection ADP-heptose shows great potential to regulate the H. pylori-induced inflammatory response in DCs.

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