Decipehering the intesitinal dual oxidase (DUOX) signaling pathway in the model pest beetle Tribolium castaneum

• Applicant: Professor Dr. Hans Merzendorfer
• Subject Area: Animal Physiology and Biochemistry
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574879782

Intestinal systems have a particular large surface to facilitate absorption of nutrients, which renders the tissues susceptible for infections by various pathogens. Infections are effectively fought by the intestinal innate immune system, which is based on conserved immune signaling pathways triggering epithelial inflammation, activation of immune cells, secretion of antimicrobial peptides and production of reactive oxygen species (ROS). The production of ROS is triggered by a pathway which involves the activation of dual oxidase (DUOX), a NADPH-dependent oxidase producing hydrogen peroxide and other ROS such as hypochlorous acid that prevents bacterial growth and contributes to the maintenance of microbial homeostasis. How DUOX is precisely activated is not known. In insects it has been shown that next to classical pathogen associated patterns, uracil can stimulate DUOX expression and trigger DUOX activation. However, the receptor for uracil was unknown. In our recent work, we have identified a G-protein coupled receptor (TcGPCR41) expressed in the midgut of Tribolium castaneum that is required for uracil-dependent DUOX expression and activation. In this project we aim to analyze TcGPCR41 in detail and compare the DUOX pathway of Tribolium with that of Drosophila melanogaster, where Malpighian tubules have been implicated in ROS production. Therefore, we aim to (1) identify the cell types expressing TcGPCR41 and producing ROS in Tribolium and Drosophila, (2) analyze the crosstalk between different immune signaling pathways stimulating DUOX activity and expression, (3) express TcGPCR41 in a heterologous system and analyze its binding properties for uracil and other ligands like Natalisin that was reported to be a ligand of the TcGPCR41 ortholog from Drosophila, and finall y(4) examine the role of the TcGPCR41 ortholog in the activation of DUOX in Drosophila using genetic tools. Eventually, we seek to decipher an important innate immune signaling pathway in insects that is known to be involved in inflammatory bowel disease in human.

• DFG Programme: Research Grants
• Co-Investigator: Privatdozent Dr. Heiko Harten