SFB/TRR 237 "Nucleic Acid Immunity"

© TRR 237

Nucleic Acid Immunity describes a fundamental mode of innate immune defence that recognises and responds to nucleic acids as signals of infection, cellular stress, or tissue damage. It reflects a central biological principle: nucleic acids are both essential molecules of life and potent immunogenic signals. This inherent duality defines Nucleic Acid Immunity as a core function of the innate immune system, which must efficiently detect foreign nucleic acids while tightly controlling aberrant self nucleic acids to ensure host protection and immune homeostasis. 

Over the first two funding periods, this consortium has established itself as an internationally leading centre by pursuing an integrative research approach. Through the combined expertise of an interdisciplinary and highly complementary team, we have defined non-self features of nucleic acids recognised by innate sensors and restriction factors, revealed how nucleic acid-metabolising systems act as key regulators of self/non-self discrimination, and dissected the molecular, subcellular, and organismal organisation of nucleic acid sensing and signalling pathways. Systems-level analyses in mouse models and human patients have enabled us to characterise dysregulated nucleic acid immune responses and to elucidate the molecular pathology of novel monogenic disorders of nucleic acid immunity, thereby linking fundamental mechanisms to pathophysiology. These insights have driven clinical translation: inhibition of Janus kinases or the IFN-α receptor has proven effective in treating type I IFN-mediated inflammation, and assessment of the blood IFN signature has been implemented as a biomarker in clinical guidelines for interferonopathies. Moreover, our work has informed several clinical studies addressing interferonopathies.

Building on this strong foundation, the third funding period aims to expand our research programme from molecular mechanisms to a systems-level understanding of Nucleic Acid Immunity and to establish it further as a fundamental biological principle at the interface of infection, sterile inflammation, autoimmunity, and cancer. We will investigate how Nucleic Acid Immunity is embedded within cellular metabolism, innate immune memory, and cell fate decisions, and how it is shaped by biophysical principles of self-organisation. A major goal is to define how maladaptive regulation of these processes drives chronic inflammation, organ pathology, and the breakdown of immune homeostasis. Through close integration with clinical research, we aim to extend insights from rare inborn errors of immunity to more common inflammatory diseases and to translate basic discoveries into novel therapeutic concepts. Our long-term vision is to establish Nucleic Acid Immunity as a paradigm for understanding how molecular danger sensing is integrated into human physiology and to define the determinants that distinguish protective from pathogenic immune responses, thereby advancing precision immunology.

For more information, please see press release.