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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 NF\u03baB-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.<\/jats:p>","DOI":"10.64898\/2026.04.06.716590","type":"posted-content","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T01:00:36Z","timestamp":1775696436000},"source":"Crossref","is-referenced-by-count":0,"title":["Viral Microglia Reprogramming Clears Oligomeric Neurotoxic Debris"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0448-3989","authenticated-orcid":false,"given":"Griffin P.","family":"Carter","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9198-9891","authenticated-orcid":false,"given":"Zachary P.","family":"McKay","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2438-4542","authenticated-orcid":false,"given":"Mark A.","family":"Katz","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9220-4293","authenticated-orcid":false,"given":"Lisbeth","family":"Disla","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9523-3445","authenticated-orcid":false,"given":"Dasean T.","family":"Nardone-White","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6465-3869","authenticated-orcid":false,"given":"Derek","family":"Southwell","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3957-1164","authenticated-orcid":false,"given":"Michael C.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4538-0302","authenticated-orcid":false,"given":"Matthias","family":"Gromeier","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC 27710, USA"},{"name":"Department of Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041004300850000_2026.04.06.716590v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nn2014"},{"key":"2026041004300850000_2026.04.06.716590v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/35099560"},{"key":"2026041004300850000_2026.04.06.716590v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-3806(99)00113-3"},{"key":"2026041004300850000_2026.04.06.716590v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.07.001"},{"key":"2026041004300850000_2026.04.06.716590v1.5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1525528113"},{"key":"2026041004300850000_2026.04.06.716590v1.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.122.3159.105"},{"key":"2026041004300850000_2026.04.06.716590v1.7","doi-asserted-by":"crossref","unstructured":"Bordt, E.A. , C.L. 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