Viral Microglia Reprogramming Clears Oligomeric Neurotoxic Debris.

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.