Regulation of pattern recognition receptors (PRRs) and their signaling cascades
DNA damage response signaling mediated antiviral response (A09)
Project Ieader: Prof. Veit Hornung
DNA damage response (DDR) cascades entail networks of pathways that signal upon the detection of respective lesions to initiate processes geared at the restoration of genomic integrity. At the same time, a plethora of antiviral transcripts is induced in the context of DDR, which implies a direct or indirect connection of these pathways to antiviral sensing or defense. Here, we want to elucidate under what circumstances this antiviral DDR response pathway is triggered, map the underlying signal transduction cascade and characterize how it diverges or overlaps with canonical pattern recognition receptor pathways leading to antiviral immune responses.
Molecular mechanism and pathophysiology of nucleic acid induced CARD9 signaling (A10)
Project leader: Prof. Jürgen Ruland
We have previously identified unique inflammatory pathways that are activated upon RNA or DNA sensing by RIG-I-like helicases or Rad50, which are controlled by the adapter proteins CARD9 and BCL10. These pathways mediate canonical NF-κB activation for pro-inflammatory cytokine production and CARD9 can, in addition, activate type I IFN production. As the pathophysiological roles and regulatory mechanisms of CARD9/BCL10 signaling during nucleic acid induced sterile inflammation are unknown, we propose to dissect the function of CARD9/BCL10 signaling in nucleic acid-driven inflammatory disease and the regulatory mechanisms that control CARD9 signaling after cytosolic RNA or DNA detection.
Role of UNC93B1 in nucleic acid sensing TLR function (A11)
Project leader: Prof. Eicke Latz
Several members of the Toll-like receptor (TLR) family can detect DNA, RNA and their degradation products in endosomal compartments of cells and a range of checkpoints have evolved that restrict the activation of nucleic acid sensing TLRs to prevent excessive activity. We will study how UNC93B1, a protein critical for the function of endosomal TLRs, regulates the half-life of nucleic acid sensing TLRs, enables their export from the ER into the secretory pathway and promotes their correct trafficking to different endosomal sites to influence the quantity and quality of cell signaling.
Contribution of cellular stress to RNA virus PAMP recognition (A12)
Project leader: Prof. Karl-Klaus Conzelmann
This project addresses the fundamental question of how persistent RNA viruses can go unrecognized by the innate immune system. The analysis of isogenic persistent and acute rabies rhabdoviruses provided experimental evidence for the contribution of cellular stress sensors to virus PAMP recognition and induction of antiviral response. Upon determination of the types of stress involved, it will be determined whether stress can prime RLR sensors for better recognition of viral RNA, or whether endogenous danger signals (DAMPs) are produced that synergize with viral RNA in cell activation.
