Immunopathology; Myeloproliferative disease; Inflammation; Inflammatory bowel disease; Cancer; Genetic mutations; Microbes
Pastille Eva, Wasmer Marie-Hélène, Adamczyk Alexandra, Vu Vivian P., Mager Lukas F., Phuong Nhi Ngo Thi, Palmieri Vittoria, Simillion Cedric, Hansen Wiebke, Kasper Stefan, Schuler Martin, Muggli Beat, McCoy Kathy D., Buer Jan, Zlobec Inti, Westendorf Astrid M., Krebs Philippe (2019), The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer, in Mucosal Immunology
Alves Ludmila Cardoso, Berger Michael D, Koutsandreas Thodoris, Kirschke Nick, Lauer Christoph, Spörri Roman, Chatziioannou Aristotelis, Corazza Nadia, Krebs Philippe (2019), Non‐apoptotic TRAIL function modulates NK cell activity during viral infection, in EMBO reports
Mager Lukas Franz, Koelzer Viktor Hendrik, Stuber Regula, Thoo Lester, Keller Irene, Koeck Ivonne, Langenegger Maya, Simillion Cedric, Pfister Simona P, Faderl Martin, Genitsch Vera, Tcymbarevich Irina, Juillerat Pascal, Li Xiaohong, Xia Yu, Karamitopoulou Eva, Lyck Ruth, Zlobec Inti, Hapfelmeier Siegfried, Bruggmann Rémy, McCoy Kathy D, Macpherson Andrew J, Müller Christoph, Beutler Bruce, et al. (2017), The ESRP1-GPR137 axis contributes to intestinal pathogenesis, in eLife
, 6, 1.
Wasmer Marie-Hélène, Krebs Philippe (2017), The Role of IL-33-Dependent Inflammation in the Tumor Microenvironment, in Front. Immunol.
, 7(-), 1-13.
Mager Lukas F., Wasmer Marie-Hélène, Rau Tilman T., Krebs Philippe (2016), Cytokine-Induced Modulation of Colorectal Cancer, in Frontiers in Oncology
, 6, 1/96-18.
Kirsten D. Mertz, Lukas F. Mager, Marie-Hélène Wasmer, Philippe Krebs (2015), The IL-33/ST2 pathway contributes to intestinal tumorigenesis in humans and mice, in OncoImmunology
, 5(1), 1-11.
Blasius Amanda L., Krebs Philippe, Sullivan Brian M, Oldstone Michael B, Popkin Daniel L. (2012), Slc15a4, a Gene Required for pDC Sensing of TLR Ligands, Is Required to Control Persistent Viral Infection, in PLOS Pathog
, 8 (9), 1002915.
Mager Lukas, Riether Carsten, Schürch Christian, Banz Yara, Wasmer Marie-Hélène, Stuber Regula, Theocharides Alexandre, Li Xiaohong, Xia Yu, Hirohisa Saito, Nakae Susumu, Baerlocher Gabriela, Manz Markus, McCoy Kathy, Macpherson Andrew, Ochsenbein Adrian, Beutler Bruce, Krebs Philippe, IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms, in The Journal of Clinical Investigation
MOLECULAR DISSECTION OF MICROBE-INDUCED IMMUNOPATHLOGYBackground and rationale: Innate and adaptive immunity are complementary systems indispensable for the survival of higher metazoans against infections. Recognition of foreign (or “danger”) molecules is a critical step to initiate an inflammatory reaction leading to the induction of defense mechanisms. Yet immuno-regulation is not of lesser importance, as it prevents exacerbated inflammation that may result in chronic inflammation and detrimental immunopathology. Genetic mutations or polymorphisms shape the extent of an inflammatory response. Therefore, both the genetic susceptibility of a host and the virulence of the invading pathogen(s) will determine the outcome of an inflammatory reaction. Chronic inflammation of microbial etiology has been suggested as the underlying cause of several debilitating conditions, particularly in patients afflicted with inflammatory bowel disease (IBD) or certain forms of malignancies. Gastric cancer has been associated with Helicobacter pylori infection, cervical cancer with human papilloma virus and hepatocellular carcinoma with hepatitis virus B and C, for instance. It is therefore essential to determine the parameters modulating host / microbes interactions in such disorders.Working hypothesis: In this project, we will work along the central hypothesis that microbes, including commensals, represent a major cause for inflammation-induced immunopathology in genetically susceptible individuals. To address this issue, we will use two distinct, recently identified mouse mutants with defined genetic alterations affecting the hematopoietic and the radio-resistant compartment, respectively. Specific aims: The major aim of this research project is to provide a detailed analysis of the molecular and cellular processes involved in microbe-associated pathogenesis in a model of myeloproliferative disorder and a model of IBD. Both are characterized by inflammatory conditions elicited by microbes and both may serve as models for microbe-triggered neoplasia.Specifically, we will investigate the ways cross-talk between Toll-like receptor (TLR) signaling and the phosphoinositide pathway using an unbiased genetic approach. We will also mechanistically evaluate how disruption of distinct central components of TLR signaling can counteract fatal myeloproliferative disease and whether commensals may instigate this disorder in mice deficient in the inositol phosphatase SHIP1.Furthermore, we will elucidate the role of a mutated allele of Esrp1, an epithelium-specific splicing regulator, for the development of IBD, and potentially colorectal cancer.Expected significance: The intended studies will use two novel mouse mutants to dissect key factors that may modulate hyperproliferation of myeloid cells and/or contribute to immunopathology exacerbated by chronic inflammatory conditions. We anticipate that the planned investigations will not only extend our current knowledge on the role of microorganisms as trigger of inflammatory disorders and cancer; they may also help to develop treatment strategies with potential translation into the clinic or to define new genetic markers of disease susceptibility, thereby allowing targeted preventive care.