Projects
We are investigating how the antiviral cytokine type I interferon (IFN) can cause diseases and how to treat such conditions!
1. Cell-intrinsic regulation of nucleic acid sensing
We are trying to understand molecular mechanisms of nucleic acid driven inflammation. This is greatly facilitated by our expertise in generating and analyzing genetically engineered mouse models of human genetic conditons. We address open questions about the relationship between aberrant innate sensing of endogenous nucleic acids, genome stability, and cancer development. Currently we are focussing the intracellular enzyme SAMHD1. This protein regulates the amount of dNTPs, the building blocks of DNA during genome replication. As a secondary function, SAMHD1 helps to progress with DNA replication, in case the the replication machinery encounters regions in the DNA that are difficult to replicate, eg. due to damaged DNA. Loss of SAMHD1 causes various phenotyes: 1. Cells with defective SAMHD1 sponatneously produce type I IFN. This causes the human autoimmune disease Aicardi-Goutières syndrome, which is related to Systemic lupus erythematosous (SLE). 2. In the absence of SAMHD1 there is more DNA damage. Interestingligy, mutations in SAMHD1 have been found in various cancers. 3. SAMHD1-deficient cells have high levels of dNTPs, which disturbs replication and allows for enhanced replicaiton viruses that use dNTPs of the cells to replciate their genomes, like HIV. If and how these observations are interconnected, is a major focus of our current research.
2. Pathogenic IFN signaling
While our first research focus investigates cell-intrinsic mechanisms that cause spontaneous activation of IFN-inducing intracellular nucleic acid sensors, in our second focus we address mechanisms that are directly caused by excessive release of type I IFN. IFN has pleitropic effects, which can lead to the activation of immune cells, restriction of viruses or it can induce programmed cell death. It is easy to imagine that prolonged activity IFN signaling can cause collateral damage and contribute to immune pathology. However, the scenarios in which a benifcial IFN response turns into a detrimental immune activation that can drive life threatening diseases are largely unknown. We are addressing how cellular sources of IFN and different contexts of IFN production (virus infection, genome instability) might contribute to the developement of IFN-driven conditions. Sensing of IFN activates a transcriptional network that consits of hundrets of interfeorn-stimulated genes (ISGs). The exact function of most ISGs is not known to date. We belive that investigating the function of ISGs holds the key to understand the different immune pathologies that are associated with chronic type I interferon production.
3. Therapeutic Regulation of IFN production
We previously demonstrated that small molecule inhibition of STING can ameliorate systemic autoimmunity. This observation had major translational implications and we will continue investigating these aspects of our findings on regulatory mechanisms of nucleic acid sensing pathways. We focus on pre-clinical evaluation of antagonists that specifically block activation of innate sensors like STING, but also other related target proteins as potential therapeutic strategies in nucleic acid driven inflammation. On the other hand, targeted activation of these pathways can be harnessed to boost anti-tumor immunity and it could increase resistance to viral infections. To this end, we are investigating how tissue-specific activation of the cGAS/STING pathway might help to overcome current limitations in cancer immunotherapy and antiviral immunity.
4. In vivo Genome Engineering
As memebers of the CRISRP/Cas Factility of the TUD, we provide help in generating model organisms for other researchers.