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To define the molecular features underlying CZS in a relevant human cell model, we evaluated ZIKV infection and neurodevelopment in primary fetal brain explants and induced pluripotent stem cell-derived mixed neural cultures at single cell resolution. We identified astrocytes as key innate immune sentinel cells detecting ZIKV and producing IFN-\u03b2. In contrast, neural progenitor cells displayed impaired innate immunity and supported high levels of viral replication. ZIKV infection of neurons suppressed differentiation and synaptic signaling networks and programmed a molecular switch from neurogenesis to astrogliogenesis. We identified a universal ZIKV-driven cellular stress response linked to intrinsic apoptosis and regulated by IFN-\u03b2. These findings reveal how innate immune signaling intersects with ZIKV-driven perturbations in cellular function to influence CZS outcomes including neuron developmental dysfunction and apoptotic cell death.<\/jats:p>","DOI":"10.1101\/2024.09.27.615512","type":"posted-content","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T18:30:12Z","timestamp":1727721012000},"source":"Crossref","is-referenced-by-count":1,"title":["The Human Neural Cell Atlas of Zika Infection in developing human brain tissue: viral pathogenesis, innate immunity, and lineage reprogramming"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3741-0057","authenticated-orcid":false,"given":"Caleb","family":"Stokes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8721-8701","authenticated-orcid":false,"given":"Leanne 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