Dokument: The role of the AhR signaling pathway in host responses to Salmonella Typhimurium infection and in tuft cell-mediated intestinal immunity
| Titel: | The role of the AhR signaling pathway in host responses to Salmonella Typhimurium infection and in tuft cell-mediated intestinal immunity | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=69861 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20260728-083331-4 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Mayer, Michelle [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Förster, Irmgard [Gutachter] Prof. Dr. Hegemann, Johannes [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that integrates environmental, dietary, microbial, and metabolic cues to control various biological processes. AhR activation induces the expression of its repressor (AhRR) and the xenobiotic-metabolizing cytochrome P450 (CYP) enzymes, which regulate AhR activity by metabolizing AhR ligands. The influence of the AhR on the outcome of infectious diseases strongly depends on the type of pathogen and the local context. In this thesis, it was studied how modulation of AhR signaling impacts host responses to Salmonella Typhimurium (STM) infection and the tuft cell-mediated intestinal immunity.
Infection of mice with the attenuated STM strain TAS2010 leads to a chronic systemic disease that resembles human typhoid fever. AhR-deficient (AhR-/-) mice were highly susceptible to TAS2010 infection compared to wildtype mice as indicated by increased bacterial burden and mortality. Furthermore, STM infection led to macrocytic anemia in AhR-/- mice and induced elevated extramedullary erythropoiesis in the spleen. This resulted in enhanced splenomegaly in AhR-/- mice, which was mainly caused by a vast expansion of immature erythroid cells and accompanied by a destruction of the splenic microarchitecture. Elevated serum levels of erythropoietin upon infection as well as increased numbers of splenic stress erythroid progenitors already in steady state probably drive this effect, which might be causative for the splenic remodeling, thereby disturbing an effective host defense of AhR-/- mice against STM infection. The small intestinal epithelium contains a rare taste-chemosensory cell type, named tuft cell. By acting as luminal sentinels, tuft cells are crucial to induce type 2 immunity to helminths. Upon helminth infection, tuft cell-derived interleukin (IL)-25 activates type 2 innate lymphoid cells (ILC2s) to secrete IL-13, which drives tuft cell hyperplasia. In mouse epithelial-only intestinal organoids used as in vitro model, AhR activation reduced IL-13-mediated tuft cell expansion. In line, enhanced AhR activity in the absence of the AhR-dependent CYP enzymes in vivo also decreased tuft cell numbers, whereas global AhR deficiency enhanced the frequency of intestinal tuft cells in steady state. In contrast to the in vitro results, activation of the whole tuft cell-ILC2 circuit by succinate treatment was significantly restrained in AhR-/- mice. These results demonstrate that an inclusion of immune cells, especially ILC2s, in organoid systems is essential to better model the tuft cell-mediated intestinal immunity. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 28.07.2026 | |||||||
| Dateien geändert am: | 28.07.2026 | |||||||
| Promotionsantrag am: | 22.01.2025 | |||||||
| Datum der Promotion: | 23.05.2025 |
