Neuronal viral reactivation as a pathogenic driver of neurodegeneration: The dual-hit viral latency hypothesis
Project title: Neuronal viral reactivation as a pathogenic driver of neurodegeneration: The dual-hit viral latency hypothesis
Call title: VolkswagenStiftung - NEXT – Rethink Neurodegeneration!
Funding source: VolkswagenStiftung
Main applicant:Prof. Dr. Martin Korte, PhD., Technische Universität Braunschweig
Coordinator: Technische Universität Braunschweig
Project partners:
- Prof. Ilija Brizić, PhD, University of Rijeka, Faculty of Medicine
- Shirin Hosseini, Ph.D., Technische Universität Braunschweig
- Eva Szegö, Ph.D., Deutsches Zentrum für Neurodegenerative Erkrankungen
- PD Dr. Iryna Prots, Ph.D., Universitätsklinikum Erlangen
Project implementation period: : 01.01.2027 – 31.12.2029
Total project value: EUR 1.725.440,00
Budget for MEDRI: EUR 287.400,00
Brief description:
The etiopathogenesis of neurodegenerative disorders, most prominently Alzheimer’s disease (AD) and Parkinson’s disease (PD), remains incompletely delineated, with canonical models attributing neuroinflammatory cascades primarily to glial activation. We propose a dual-hit viral latency hypothesis: latent viruses, especially Herpesviridae such as cytomegalovirus (CMV), undergo neuronal reactivation following secondary perturbations (e.g., aging, toxins, psychological stress). We hypothesize that reactivation elicits neuron-intrinsic innate immune signaling, positioning neurons as initiators of neuroinflammation and drivers of neurodegeneration. To test this, we will employ human iPSC-derived neurons, brain organoids, and murine CMV latency models. Reactivation will be confirmed by NF-κB/IRF3/7 activation, immune gene induction, and secretome profiling. Neuron–glia cross-talk will be studied using conditioned media exchange and cell type–resolved transcriptomics. Causality will be addressed through neuron-specific modulation of innate immune pathways. Pathological outcomes will include neuronal loss, synaptic dysfunction, inflammatory cascades, and AD/PD[1]linked protein accumulation in vulnerable regions. By reframing immune activation as neuron-initiated rather than glia-driven, this high-risk/high-gain project offers a framework for selective vulnerability and a rationale for antiviral or immunomodulatory therapies.
