Viral infections have been recently associated with the development of neuropathological diseases, prominently neurodegenerative disorders. Of note, both neurotropic and non-neurotropic viruses were shown to drive diseases. However, the molecular mechanisms as well as viral and immunological determinants that drive the neuropathological impact of viruses are so far little understood. We are using our expertise in understanding the impact of (neurotropic) viral infections on cerebral organoid models, primary cell cultures and cell line models to mechanistically dissect viral manipulation of inflammation, proteostasis and cellular energy homeostasis.

Excessive or chronic innate immune response, both sterile or pathogen-induced inflammation, play a key role in the development of neurodegenerative diseases. Increasingly, research is uncovering molecular mechanisms that highlight the role of inflammation in pathogenesis. To explore this further, we study monogenic inflammatory diseases associated with neuropathology to better understand the detrimental impact of inflammation. Interestingly, recent findings have also revealed protective aspects of innate immune activation in combating neurodegeneration. As a result, our research also focuses on unraveling the molecular mechanisms that govern the balance between protection and pathology in neurodegenerative diseases. To this end, we use patient-derived cells, patient organoid models and detailed mechanistic dissection of the involved signaling cascades using a combination of spatial and interactome analyses.

Building on our insights into the molecular biology of innate immunity in both defense and disease, we aim to precisely modulate immune responses as a therapeutic strategy—mitigating detrimental inflammation while enhancing protective responses. To identify and refine highly specific molecules, we tap into the vast resource of the human peptidome. Chromatographically separated fractions from human source material are analyzed for immunomodulatory properties in a medium-to-high throughput manner. Through iterative purification and reanalysis of bioactive fractions, we aim to identify the active peptide(s). These peptides are synthesized in-house and systematically studied to understand their mechanisms. As highly flexible biopolymers, the candidate peptides will be optimized for function using a combination of systematic approaches and computational modeling, with their therapeutic potential explored in organoid models.

Genome analyses in the recent decade have unraveled many mutations in risk genes that are associated with the development of neurodegenerative diseases. To repair pathogenic variants, various techniques ranging from gene expression suppression via shRNAs or editing using CRISPR/Cas9 type systems (e.g. CRISPR PRIME) can be applied. A significant challenge lies in delivering these systems to neurons. Our approach leverages naturally neurotropic viruses as gene therapy vectors. We aim to dissect the tropism of several neurotropic viruses (e.g., lyssaviruses, polyomaviruses, flaviviruses), study their molecular biology, and load recombinant viruses with therapeutic cargo. Additionally, we enhance the targeting of commonly used gene therapy vectors like AAVs and LVs by incorporating naturally neurotropic viral glycoproteins. These vectors are optimized and produced for potential therapeutic applications.