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SFB 670:  Cell-Autonomous Immunity

Subject Area Biology
Agriculture, Forestry and Veterinary Medicine
Medicine
Term from 2006 to 2018
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 13123509
 
Final Report Year 2019

Final Report Abstract

Immunity against microbial pathogens primarily depends on the recognition of pathogen components by innate receptors expressed on immune and non-immune cells. Innate receptors are evolutionarily conserved germ-line-encoded proteins and include TLRs (Toll-like receptors), NLRs (Nod-like receptors), and RLRs (RIG-I (retinoic acid-inducible gene-I)-like receptors). These families of receptors are collectively known as PRRs (pattern-recognition receptors), which recognize the specific molecular structures of pathogens known as PAMPs (pathogen-associated molecular patterns, also called microbe-associated molecular patterns (MAMPs)) in various compartments of cells, such as the plasma membrane, the endolysosome and the cytoplasm. The activation of these receptors results in induction of cell-autonomous antimicrobial effector mechanisms and in expression of cytokines, chemokines and co-stimulatory molecules, which also contribute to the elimination of pathogens and instruction of pathogen-specific adaptive immune responses. In plants and animals, the NLR family of receptors perceives non-self and modified-self molecules inside host cells and mediates innate immune responses to microbial pathogens. An inflammatory response often requires additional stimuli elicited by endogenous molecules termed “damage-associated molecular patterns” (DAMPs). DAMPs are released by necrotic cells and include HMGB1, IL-1α, uric acid, DNA fragments, mitochondrial content, and ATP. Despite similar biological functions and molecular architecture, animal NLRs are, in general, activated by conserved microbe- or damage-associated molecular patterns, whereas plant NLRs typically detect strain-specific pathogen effectors. Plant NLRs recognize either the effector structure or effector-mediated modifications of host proteins. The latter indirect mechanism for the perception of non-self, as well as the within-species diversification of plant NLRs, maximize the capacity to recognize non-self through the use of a finite number of innate immunoreceptors. In the three funding periods, the CRC 670 furthered in a substantial, internationally recognized way the understanding of the activation, function and effector mechanisms of autonomous immune responses of animal and plant cells with important impact on the understanding of the innate immune system in general. Special emphasis had been devoted to cell type-specific and autonomous defense reactions in immune and non-immune cells, which added additional layers of complexity to our understanding of innate immunity. Key results include the i) characterization of molecular mechanisms underlying the co-operation of TLRs, NLRs, RLRs, and DAMPs in plant and animal cells; ii) the identification and characterization of ligand specificities of cytosolic DNA (cGAS) and RNA receptors (RLRs) and elucidation of their signal transduction pathways; iii) a new understanding of the physiologic significance of various forms of cell death with respect to release of DAMPs and inflammasome activation; and iv) novel insights into the cell type- and pathogen-specific activation requirements for autophagy and its functional impact during phagocytosis and host cell defense. The CRC 670 has contributed to, and was strongly supported by a unique immunological community and infrastructure in Cologne and Bonn. Some principal investigators received calls for prestigious academic positions from internationally respected institutions. The excellent expertise of scientists newly recruited for replenishing the CRC faculty enabled us to continuously tackle highly competitive questions in cell-autonomous immunity. With its unique, cooperative setting and intellectual exchange of plant and animal scientists, the CRC 670 has built the scientific capacity that will continue to make important observations in the field leading to new concepts and questions in innate immunity. Indeed, Gunther Hartmann and other PIs of the CRC 670 established the cluster of excellence "ImmunoSensation" at the University of Bonn. Plant immunity to microbes is an integral research area of the Cluster of Excellence "CEPLAs" co-founded by Paul Schulze-Lefert. Eventually, the CRC 670 has played a pivotal role in attracting the German Center for Infection Research (DZIF) to the unversities of Cologne and Bonn that fosters the translation of basic science into clinically applicable preventive, diagnostic or therapeutic modalities in infectious diseases. Clearly, the chapter of innate immunity is not closed after the termination of the CRC 670, neither locally nor as a valuable research topic in general.

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