Characterization and mathematical modeling of the pathogenic IFN response caused by defects of the Aicardi-Goutières syndrome gene SAMHD1.

• Applicant: Professor Dr. Rayk Behrendt
• Subject Area: Immunology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 325560868

In recent years it has become clear that aberrant innate immune signaling can cause systemic autoimmune conditions. Cytokines produced after signaling of pattern recognition receptors (PRRs) are key players that drive the loss of self-tolerance and among these, type I interferons (IFN) have been demonstrated to have a pivotal role. In a healthy organism they represent the first line of antiviral defense and are induced upon signaling of different innate immune receptors that preferentially detect nucleic acids. Mutations in intracellular nucleic acid metabolizing enzymes such as TREX1, RNAse H2, ADAR and SAMHD1 have been shown to cause the rare autoimmune disorder Aicardi-Goutières syndrome (AGS), which is characterized by pathogenic IFN production triggered by accumulation of endogenous nucleic acids, substrates of these enzymes. However, their substrates differ and consequently it now seems that IFN production caused by loss of one of these enzymes leads to pathogenic signaling events that involve distinct pathways. Here, we investigate the signaling events that underlie the chronic IFN production in the absence of SAM and HD domain containing 1 (SAMHD1). In Samhd1-deficient mice we found that cytoplasmic RNA and DNA sensing pathways are essential for the spontaneous activation of the IFN system. This result is in sharp contrast to the findings in other AGS-models in which IFN production only requires either a functional RNA or a functional DNA sensing pathway in the cytoplasm. To understand this phenomenon we will combine cell biology experiments with mathematical modeling of intracellular nucleic acid sensing mediated by the Rig-like receptor (RLR) and the cGAS-STING pathways, which detect cytoplasmic RNA and DNA, respectively. We will generate quantitative, time resolved data for essential pathway components activated in response to specific nucleic acid stimuli and in response to the loss of SAMHD1. Furthermore, we will apply genetic engineering in immortalized SAMHD1-deficient mouse embryonic fibroblasts (MEF) to characterize the pathways that mediate the IFN production. This data will feed into the development of a mechanistic mathematical model describing the dynamics of pathway activation and transcriptional regulation in response to exogenic nucleic acids and in response to the loss of SAMHD1. We aim to understand the cellular process in which SAMHD1 is essential to prevent aberrant activation of the innate immune system. Additionally, our study will yield a valuable tool that allows for in silico modeling of innate immune responses caused by detection of intracellular RNA or DNA, arising with defects of intracellular nucleic acid waste disposal mechanisms or in the course of viral infections. This project might therefore be of relevance not only for subsequent research in type I IFN-dependent genetic autoimmune conditions but also for infectious disease research.

• DFG Programme: Research Grants