Characterization and mathematical modeling of the pathogenic IFN response caused by defects of the Aicardi-Goutières syndrome gene SAMHD1.
Final Report Abstract
In our project we investigated how inappropriate inactivation of intracellular nucleic acid sensors, which normally defend us against viruses, can cause genetic inflammatory diseases. This happens if the virus sensors mistake our own genetic material, like DNA or RNA for viral nucleic acids and thus constantly mount an antiviral immune response. We found that the amount of a sensor that detects a specific type of RNA is rapidly increased as soon as the cell detects DNA in its cytosol. We also found that blocking the innate immune sensing pathway that detects DNA in the cytosol, can ameliorate the disease in a mouse model which develops chronic inflammation due to the loss of the cytosolic DNA-degrading enzyme called Trex1. It is very likely that this strategy will be further developed into an actual treatment for inflammatory or autoimmune diseases that are caused by an inappropriate immune response against the cell´s own DNA. In another mouse model for the same type of inflammatory disease, but which lacks a different gene called Samhd1, we found that not all of the falsely induced immune response is mounted against DNA. In this model, we observed that the RNA sensor, which we earlier found to be rapidly induced in response to the detection of DNA in the cytosol of cells, is chronically activated. So far, the disease-inducing immune response in patients and mice lacking Samhd1 was only reported to be caused by erroneous sensing of endogenous DNA. Our data suggest that a more complex mechanism is contributing to the disease caused by lack of Samhd1 compared to the loss of Trex1. Our data also suggest that the intracellular DNA and RNA sensing pathways are functionally linked. We will explore these findings in more detail in the future to better understand the relationship between DNA and RNA sensing in the development of nucleic acid-driven inflammation and therapies thereof.
Publications
- Targeting STING with covalent small-molecule inhibitors. Nature. 2018 Jul;559(7713):269-273
Haag SM, Gulen MF, Reymond L, Gibelin A, Abrami L, Decout A, Heymann M, van der Goot FG, Turcatti G, Behrendt R, Ablasser A
(See online at https://doi.org/10.1038/s41586-018-0287-8)
