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TRR 237:  Nucleic Acid Immunity

Subject Area Medicine
Biology
Term since 2018
Website Homepage
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 369799452
 
All life forms have developed sophisticated mechanisms to recognize and eliminate foreign genetic material. In recent decades, this research has followed three main directions: nucleic acid (NA) immune sensing receptors, antiviral restriction factors, and NA metabolism. However, current advances have led us to realise that they are all integral parts of a larger NA defence system, which we refer to as Nucleic Acid Immunity. With this consortium, we are taking an integrative and holistic approach to explore the mechanisms and functional consequences of Nucleic Acid Immunity. On the one hand, we focus on gaining fundamental insights into the specific molecular mechanisms that control the defence against pathogen-derived foreign NAs, and on the other hand, we address the functional role of this system in health and disease at the systemic level of the whole organism. Here, special emphasis is placed on the implications of Nucleic Acid Immunity for viral infections, and for sterile inflammatory conditions. Furthermore, rare monogenic diseases caused by dyshomeostasis of Nucleic Acid Immunity offer unprecedented insights into the inner workings of this intricate system.With an interdisciplinary and highly complementary team of scientists, we are in a unique position to answer pressing questions in this field: i) What are the exact non-self features in NAs that are being detected by NA sensors or restriction factors? ii) How do NA-metabolizing systems govern or contribute to self vs. non-self discrimination? iii) How are threshold behaviours of NA sensors and restriction systems realised at the molecular level? iv) How is the subcellular positioning and trafficking of NA sensors regulated and how do their signalling cascades operate? v) How do defects of NA sensing and metabolism trigger systemic autoimmunity and what counter-regulatory mechanisms exist? vi) What determines the immunogenicity of NAs in the context of infection and vaccination and how can these features be leveraged for NA-based therapies? vii) Employing systems approaches, can we identify minimal endotypes in patients suffering from dysregulated NA immune responses, and how can these inform us about the underlying pathophysiology and guide therapy? viii) Having learned much from rare monogenic diseases, can we also identify common genetic variants to understand interindividual heterogeneity in Nucleic Acid Immunity?The results of our work will not only enable fundamental insights into the functioning of the immune system, but also provide important building blocks for the development of new diagnostic and therapeutic concepts for a variety of important diseases including viral infection, sterile inflammatory conditions, and cancer. As a future perspective, we aim at translating these insights into novel molecularly informed clinical applications to achieve accurate diagnosis, patient stratification and targeted therapies thus accelerating the implementation of precision immunology.
DFG Programme CRC/Transregios

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Spokespersons Professor Dr. Gunther Hartmann, until 12/2022; Professor Dr. Veit Hornung, since 1/2023
 
 

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