SFB 670: Cell-Autonomous Immunity
Agriculture, Forestry and Veterinary Medicine
Medicine
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.
Publications
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Eicke Latz
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Eicke Latz
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Eicke Latz
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Eicke Latz
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(See online at https://doi.org/10.1038/nature12640) - (2013) cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING. Nature 498: 380-384
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(See online at https://doi.org/10.1038/nature12452) - 12004666.9-2405. 5’triphosphate oligonucleotide with blunt end and uses thereof. PCT/EP2013/07011 Novel RIG-I ligands and methods for producing them
Gunther Hartmann, Martin Schlee
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(See online at https://doi.org/10.1038/ncb3071) - (2014) RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513:90-94
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(See online at https://doi.org/10.1038/nature13608) - (2014) The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nature Immunol 8:727-737
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(See online at https://doi.org/10.1038/ni.2913) - (2015) A conserved histidine in the RNA sensor RIG-I controls immune tolerance to N1-2’O-methylated self RNA. Immunity. 43(1): 41-51
Schuberth-Wagner C, Ludwig J, Bruder AK, Herzner AM, Zillinger T, Goldeck, M, Schmidt T, Schmid- Burgk L, Kerber R, Wolter S, Stümpel JP, Roth A, Bartok E, Drosten C, Coch C, Hornung V, Barchet W, Kümmerer BM, Hartmann G, Schlee M
(See online at https://doi.org/10.1016/j.immuni.2015.06.015) - (2015) A receptor pair with an integrated decoy converts pathogen disabling of transcription factors to immunity. Cell 161: 1074-1088
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(See online at https://doi.org/10.1016/j.cell.2015.04.025) - (2015) Necroptosis and its role in inflammation. Nature 517:311-320
Pasparakis M, Vandenabeele P
(See online at https://doi.org/10.1038/nature14191) - 20100120894. Intracellular DNA receptor, United States
Eicke Latz
- (2016) Allelic barley MLA immune receptors recognize sequence-unrelated avirulence effectors of the powdery mildew pathogen. PNAS 113(42):E6486–E6495
Lu X, Kracher B, Saur IML, Bauer S, Ellwood SR, Wise R, Yaeno T, Maekawa T, Schulze-Lefert P
(See online at https://doi.org/10.1073/pnas.1612947113) - (2016) Human Monocytes Engage an Alternative Inflammasome Pathway. Immunity 44, 833-846
Gaidt MM, Ebert TS, Chauhan D, Schmidt T, Schmid-Burgk JL, Rapino F, Robertson AA, Cooper MA, Graf T, Hornung V
(See online at https://doi.org/10.1016/j.immuni.2016.01.012) - (2016) NEMO Prevents RIP Kinase 1-Mediated Epithelial Cell Death and Chronic Intestinal Inflammation by NF-κB-Dependent and -Independent Functions. Immunity 44:553-567
Vlantis K, Wullaert A, Polykratis A, Kondylis V, Dannappel M, Schwarzer R, Welz P, Corona T, Walczak H, Weih F, Klein U, Kelliher M, Pasparakis M
(See online at https://doi.org/10.1016/j.immuni.2016.02.020) - (2017) Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease. Nature. 552:355-361
Venegas C, Kumar S, Franklin BS, Dierkes T, Brinkschulte R, Tejera D, Vieira-Saecker A, Schwartz S, Santarelli F, Kummer MP, Griep A, Gelpi E, Beilharz M, Riedel D, Golenbock DT, Geyer M, Walter J, Latz E, Heneka MT
(See online at https://doi.org/10.1038/nature25158) - (2017) Pathogen exploitation of an abscisic acid- and jasmonate-inducible MAPK phosphatase and its interception by Arabidopsis immunity. Proc Natl Acad Sci USA 114: 7456-7461
Mine A, Berens ML, Nobori T, Anver S, Fukumoto K, Winkelmüller TM, Takeda A, Becker D, Tsuda K
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(See online at https://doi.org/10.1016/j.stem.2016.12.005) - (2017) The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell Death Program Upstream of NLRP3. Cell 171:1110-1124
Gaidt MM, Ebert TS, Chauhan D, Ramshorn K, Pinci F, Zuber S, O'Duill F, Schmid-Burgk JL, Hoss F, Buhmann R, Wittmann G, Latz E, Subklewe M, Hornung V
(See online at https://doi.org/10.1016/j.cell.2017.09.039) - (2018) Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis. Nat Comm 9: 4805
Welz M, Eickhoff S, Abdullah Z, Trebicka J, Gartlan KH, Spicer JA, Demetris AJ, Akhlaghi H, Anton M, Manske K, Zehn D, Nieswandt B, Kurts C, Trapani JA, Knolle P, Wohlleber D, Kastenmuller W
(See online at https://doi.org/10.1038/s41467-018-07213-x) - (2018) Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov. 9:588-606 5
Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E
(See online at https://doi.org/10.1038/nrd.2018.97) - (2018) The Chaperone UNC93B1 regulates Toll-like receptor stability independent of endosomal TLR transport. Immunity 48(5): 911-922
Pelka K, Bertheloot D, Reimer E, Phulphagar K, Schmidt SV, Christ A, Stahl R, Watson N, Miyake K, Hacohen N, Haas A, Brinkmann MM, Marshak-Rothstein A, Meissner F, Latz E
(See online at https://doi.org/10.1016/j.immuni.2018.04.011) - (2018) The ß2 integrin Mac-1 induces protective LC3-associated phagocytosis of Listeria monocytogenes. Cell Host & Microbe 23: 324-337
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(See online at https://doi.org/10.1126/scisignal.aar5926)
