Translational discovery of novel treatments as regards to diseases of global relevance through the utilization of the wildling model and the integration of complementary high dimensional techniques

• Applicant: Professor Dr. Stephan Patrick Rosshart
• Subject Area: Gastroenterology ; Hematology, Oncology ; Immunology ; Parasitology and Biology of Tropical Infectious Disease Pathogens ; Pneumology, Thoracic Surgery
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 446316360

Laboratory mice are a mainstay of biomedical research, particularly in the field of immunology. However, current mouse models suffer from a major issue: Limited translational research value in predicting complex physiological responses of humans, e.g. the transition from preclinical studies in mice to bedside practice in humans suffers a high failure rate. While this was primarily attributed to differences in physiology and genetics between mice and humans, recent studies by myself – and others – showed that conventional laboratory mice are additionally too far removed from natural environmental conditions to faithfully mirror the physiology of free-living mammals like humans. Mammals and their immune systems evolved to survive and thrive in a microbial world and behave very differently in a sanitized environment. To address this problem, I proposed the “natural microbiota” approach which engrafts naturally co-evolved microbiota from wild mice into laboratory mice. I showed that naturally co-evolved microbiota from wild mice confer fitness promoting traits that protect from lethal Influenza A virus infection and colorectal cancer. Thus, natural microbiota-based models may lead to the discovery of novel, microbiota-mediated, protective mechanisms relevant to free-living mammalian organisms – such as humans and wild mice – that could not and that cannot be found in conventional laboratory mice. Importantly, my research proved that natural microbiota-based models (such as wildlings), but not conventional laboratory mice, phenocopy human immune responses and would have predicted the outcome of failed clinical trials. Thus, such models could have prevented the pursuit ineffective and harmful treatments at the preclinical stage: CD28-superagonist treatment for inflammatory diseases and anti-TNF-α treatment in the context of lethal sepsis. After laying the foundation for better translational research models, I have now established natural microbiota- and pathogen-based mouse models – such as wildlings – at the University Medical Center Freiburg. Wildlings are the ideal tool to shift the gear from my former conceptual and retrospective approach to a mechanistic and prospective approach in the field of translational immunological research. I realize this through a collaborative effort ideally embedded into Freiburg’s research landscape and utilize wildlings to gain novel pathophysiological and mechanistic insights into diseases of global relevance. Specifically, my study proposal consists of three independent – but connected – projects tailored to the purpose of translational research and is ultimately aiming to identify novel treatments for diseases imposing a significant global health and socioeconomic burden on humanity: Sepsis, lethal Influenza virus infection and colorectal cancer.

• DFG Programme: Independent Junior Research Groups
• Major Instrumentation: High-throughput automated cell counter
• Instrumentation Group: 3500 Zellzähl- und Klassiergeräte (außer Blutanalyse), Koloniezähler