Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Anthofer, M.
Studying Helicobacter pylori as a manipulator of the NKG2D stress and tumor surveillance system
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2024. pp. 135
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Gorkiewicz Gregor
- Strobl Herbert
- Altmetrics:
- Abstract:
- Helicobacter pylori employs numerous strategies to dampen mucosal immunity in order to facilitate its persistence in the stomach. Impaired immunity can also favor cancer development since transformed cells might escape immune recognition and grow unimpeded to overt malignancy. H. pylori is a carcinogen, whose persistence strategies and gastric carcinogenesis are likely interlinked. In this context, our research group previously found indications that H. pylori might modulate the natural killer group 2, member 2 (NKG2D) system, an important mucosal stress-detection system. NKG2D ligands are expressed by epithelial cells during infection or malignant transformation and can be detected by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) via the receptor NKG2D. Receptor-ligand binding activates lymphocyte cytotoxicity, resulting in the elimination of ligand-expressing cells. Interestingly, a range of immune evasion strategies to avoid recognition via the NKG2D system were found in cancers and in virus infections. Here we aimed to identify, whether and how H. pylori might affect the NKG2D system. By analysing human stomach tissues, we found that NKG2D-expressing cell types were not induced in H. pylori gastritis, despite major immune infiltration. In these tissues, gene expression of the receptor NKG2D was lower, while gene and protein expression of NKG2D ligands were elevated in gastritis, compared to the healthy state, indicating a dysregulation of the NKG2D system. Using cell-culture assays, we found that H. pylori induced the transcription and proteolytic shedding of NKG2D ligands in stomach epithelial cells and those effects were associated with the H. pylori virulence factors CagA and VacA. Finally, the use of an NK cell line allowed us to demonstrate, that soluble NKG2D-ligands released by H. pylori-infected epithelial cells, dampened the cytotoxic activity of effector immune cells. In conclusion, this study describes a so far unrecognized method of immune manipulation by H. pylori. NKG2D-evasion by H. pylori might contribute to the chronic infection by facilitating bacterial persistence. In addition, this mechanism might drive the development of stomach cancer by enabling transformed cells to persist. These results provide new insights into the interactions of mucosal pathogens with the host immune system and advance our understanding of tumor immune escape mechanisms, which may fuel the development of future immunotherapy approaches.