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The cellular and molecular basis of congenital ZIKV infection are not well understood. Here, we utilized a biologically relevant cell-based system of human fetal retinal pigment epithelial cells (FRPEs), hiPSC-derived retinal stem cells (iRSCs), and retinal organoids to investigate ZIKV-mediated ocular cell injury processes. Our data show that FRPEs were highly susceptible to ZIKV infection exhibiting increased apoptosis, whereas iRSCs showed reduced susceptibility. Detailed transcriptomics and proteomics analyses of infected FRPEs were performed. Nucleoside analogue drug treatment inhibited ZIKV replication. Retinal organoids were susceptible to ZIKV infection. The Asian genotype ZIKV exhibited higher infectivity, induced profound inflammatory response, and dysregulated transcription factors involved in retinal organoid differentiation. Collectively, our study shows that ZIKV affects ocular cells at different developmental stages resulting in cellular injury and death, further providing molecular insight into the pathogenesis of congenital eye disease.<\/jats:p>","DOI":"10.3390\/v15010142","type":"journal-article","created":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T02:23:06Z","timestamp":1672626186000},"page":"142","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Differential Susceptibility of Fetal Retinal Pigment Epithelial Cells, hiPSC- Retinal Stem Cells, and Retinal Organoids to Zika Virus Infection"],"prefix":"10.3390","volume":"15","author":[{"given":"Deisy","family":"Contreras","sequence":"first","affiliation":[{"name":"Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"},{"name":"Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1649-9251","authenticated-orcid":false,"suffix":"Jr.","given":"Gustavo","family":"Garcia","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa Kaye","family":"Jones","sequence":"additional","affiliation":[{"name":"Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"},{"name":"Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura E.","family":"Martinez","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akshaya","family":"Jayakarunakaran","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vineela","family":"Gangalapudi","sequence":"additional","affiliation":[{"name":"Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Wu","sequence":"additional","affiliation":[{"name":"Alpine BioTherapeutics Corporation, 11107 Roselle Street, Suite 210, San Diego, CA 92121, 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Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6332-6591","authenticated-orcid":false,"given":"Ashok","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1742-5211","authenticated-orcid":false,"given":"Karin","family":"Nielsen-Saines","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4605-8166","authenticated-orcid":false,"given":"Shaomei","family":"Wang","sequence":"additional","affiliation":[{"name":"Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, 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