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Viral Microglia Reprogramming Clears Oligomeric Neurotoxic Debris
Griffin P Carter1, Zachary P McKay2, Mark A Katz1
1Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.
Abstract:
Owing to pivotal roles in CNS debris clearance and homeostasis, microglia are central targets for the therapy of neurodegenerative diseases. Intricate proximity to neurons, the inherent danger of neuroimmune toxicity, and intrinsically high plasticity and adaptability, impose high hurdles on microglia modulation. Attenuated viruses are being tested extensively against CNS malignancies (i.e., cancer virotherapy); yet, aside from viral vector-mediated payload delivery, virotherapy for non-neoplastic CNS disease remains unexplored. Here we report disseminated targeting of microglia with the highly attenuated polio:rhinovirus chimera, PVSRIPO, that culminated in profound, durable microglia reprogramming. This phenotype, rooted in extended cytoplasmic viral (v)RNA replication, was non-cytopathogenic and did not yield virus progeny or dissemination. vRNA replication in microglia triggered selective interferon (IFN) regulatory factor (IRF) 3/IRF7 transcriptional programs in the relative absence of NFκB-driven proinflammatory cytokine responses and elicited robust phagocytosis of both tumor cells and amyloid-beta. Targeting of microglia with PVSRIPO mediated immunotherapy in a mouse glioma model and the clearance of oligomeric amyloid-beta deposits in an injectable model of neurotoxic amyloid accumulation. This work identifies attenuated virotherapy as an approach to safely and effectively invigorate microglia function in immune surveillance and neurotoxic debris clearance.
Insights
Attenuated polio:rhinovirus chimera (PVSRIPO) safely reprograms microglia, enhancing their ability to clear neurotoxic debris and tumor cells. This novel virotherapy approach invigorates microglial immune surveillance for treating neurodegenerative diseases.
Area of Science:
- Neuroimmunology
- Virotherapy
- Neurodegenerative Diseases
Background:
- Microglia are crucial for central nervous system (CNS) homeostasis and debris clearance, making them therapeutic targets for neurodegenerative diseases.
- Modulating microglia is challenging due to their proximity to neurons, risk of neuroinflammation, and inherent plasticity.
- While oncolytic virotherapy is established, its application for non-cancerous CNS diseases is unexplored.
Purpose of the Study:
- To investigate the potential of attenuated virus therapy for modulating microglial function in non-neoplastic CNS conditions.
- To assess the safety and efficacy of PVSRIPO in targeting and reprogramming microglia.
Main Methods:
- Utilized a highly attenuated polio:rhinovirus chimera (PVSRIPO) for disseminated microglial targeting.
- Analyzed viral RNA replication, non-cytopathogenic effects, and progeny virus absence.
- Examined interferon regulatory factor (IRF) and NFκB pathway activation.
- Assessed phagocytic activity against tumor cells and amyloid-beta.
Main Results:
- PVSRIPO induced profound and durable microglia reprogramming via cytoplasmic viral RNA replication.
- The reprogramming was non-cytopathogenic, without virus progeny or dissemination.
- Selective IRF3/IRF7 transcriptional programs were activated with minimal proinflammatory cytokine response.
- PVSRIPO enhanced microglial phagocytosis of tumor cells and amyloid-beta.
Conclusions:
- Attenuated virotherapy, specifically with PVSRIPO, offers a safe and effective strategy to enhance microglial function.
- This approach can invigorate microglia for improved immune surveillance and clearance of neurotoxic debris in CNS diseases.
- PVSRIPO demonstrated efficacy in a glioma model and amyloid-beta clearance models.
