Investigation of the local immune system regulation in COVID-19 Group Krebs The mechanisms leading to severe inflammatory lung disease in some COVID-19 patients are unknown. In this project, we will analyze the cells in the lung lavage of these patients and compare these findings with results from collaborators working on a mouse model of COVID-19. We hope so to reveal targets for COVID-19 therapy. Graphical abstract
Role of cytokine signaling for immunopathology and tumor development Group Krebs Inflammation is a driver of cancer. We have shown that IL-33 signaling is important for the development of myeloproliferative neoplasms (MPN), a type of blood cancer, and for promoting colorectal cancer (CRC) (Mager, J Clin Invest, 2015; Mertz, OncoImmunology, 2015; Pastille, Mucosal Immunol, 2019; Yeoh & Vu, Cytokine, 2022). We currently investigate the contribution of IL-33 to MPN progression and to the cellular and molecular mechanisms underlying IL-33-dependent CRC. For these studies, we use patient-derived samples and mouse models. Increased levels of IL-33 protein in bone marrow of MPN patients. IL-33: brown; CD34 (endothelial cells): red
mRNA splicing and epithelial integrity Group Krebs The intestinal barrier is often disrupted during intestinal diseases, causing gut leakiness. We have recently shown that the protein ESRP1, a regulator of mRNA splicing in epithelial cells, has a critical function to maintain the integrity of the intestinal barrier (Mager et al., eLife, 2017). In this project, we further investigate how loss or reduction of ESRP1 leads to intestinal homeostasis and pathogenesis, including inflammatory bowel disease and colorectal cancer. Bacteria (white arrows) penetrate the leaky intestinal barrier of Esrp1 mutant mice. Scale bars: 100 μm (from Mager et al., eLife, 2017)
Immunoregulation and immunopathology Group Krebs The vertebrate immune system comprises the innate immune system, providing the first line of defense, and the adaptive immune system, which is triggered at a later stage and is responsible for memory. In this project, we use different murine models to better understand the role of specific genes in the regulation of these immune cell subsets and how disbalance in this process may lead to immunopathology in different disease contexts, including pathogen infection (Cardoso Alves, EMBO Reports, 2020). Changes in immune infiltrate composition and transcriptomic landscape in the lungs of diseased mice with a defect in immunoregulation. A. Immune cells were isolated from lung tissues of healthy and diseased mice and analyzed by flow cytometry to distinguish between immune cell subtypes, which are displayed in a tSNE representation. B. Alternatively, lung innate immune lymphocytes were analyzed using single-cell RNA sequencing.
