PROJECT SUMMARY Inflammation has been implicated in nearly every neuropsychiatric and degenerative disease, yet neuroimmune cells remain nearly intractable by every available therapeutic strategy. Small molecule drugs consistently fail clinical trials, as neuroimmune signaling pathways have essential pleiotropic functions in neighboring cell types. Meanwhile cell type selective therapies remain elusive, as microglia, and other neuroimmune cells, are intrinsically resistant to gene therapy vectors. Overcoming these unique challenges demands a new approach to medicine, drawing from an unlikely source of neuroimmune specific bioactivity. In nature, the Zika virus (ZKV) infects microglia, suppresses inflammation, and stimulates autophagy so expertly that almost half of infections go unnoticed. If this bioactivity could be safely refined, it would offer relief for neurodegenerative disorders from Parkinson’s to Alzheimer's disease. Parsing therapeutic from pathogenic mechanisms of the ZKV genome presents much greater complexity than ever previously addressed, but recent advances make it possible. Recombinant ZKV vectors, already in use, provide starting material for synthetic biology, while new viral assisted and continuous evolution methods allow bioengineering at scales capable of reshaping whole genomes. We can harness ZKV’s microglia specific immunosuppressive mechanisms into therapies with potential beyond any current technology. This proposal presents the first steps along the path towards an entirely new kind of therapy for neurodegenerative disorders.

PROJECT NARRATIVE: Viruses have been engineered into invaluable tools for research and vehicles for therapeutics, but none effectively reach neuroimmune cells. The Zika virus offers a host of mechanisms to selectively target and suppress the intrinsic and innate immune responses of microglia, the predominant immune cell. We propose the domestication of Zika into a neuroimmune selective vector and a platform for tailored immunomodulation. The bioactivity can be harnessed into root cause therapies for the treatment of neuroinflammatory and degenerative diseases.