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dc.contributor.authorMuffat, Julien
dc.contributor.authorLi, Yun
dc.contributor.authorOmer, Attya
dc.contributor.authorBakiasi, Grisilda
dc.contributor.authorRichards, Edward
dc.contributor.authorMeyer, Aaron
dc.contributor.authorJaenisch, Rudolf
dc.contributor.authorDurbin, Ann F
dc.contributor.authorBosch, Irene
dc.contributor.authorGehrke, Lee
dc.date.accessioned2019-02-22T17:59:00Z
dc.date.available2019-02-22T17:59:00Z
dc.date.issued2018-05
dc.date.submitted2017-11
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/120543
dc.description.abstractMaternal Zika virus (ZIKV) infection during pregnancy is recognized as the cause of an epidemic of microcephaly and other neurological anomalies in human fetuses. It remains unclear how ZIKV accesses the highly vulnerable population of neural progenitors of the fetal central nervous system (CNS), and which cell types of the CNS may be viral reservoirs. In contrast, the related dengue virus (DENV) does not elicit teratogenicity. To model viral interaction with cells of the fetal CNS in vitro, we investigated the tropism of ZIKV and DENV for different induced pluripotent stem cell-derived human cells, with a particular focus on microglia-like cells. We show that ZIKV infected isogenic neural progenitors, astrocytes, and microglia-like cells (pMGLs), but was only cytotoxic to neural progenitors. Infected glial cells propagated ZIKV and maintained ZIKV load over time, leading to viral spread to susceptible cells. DENV triggered stronger immune responses and could be cleared by neural and glial cells more efficiently. pMGLs, when cocultured with neural spheroids, invaded the tissue and, when infected with ZIKV, initiated neural infection. Since microglia derive from primitive macrophages originating in proximity to the maternal vasculature, they may act as a viral reservoir for ZIKV and establish infection of the fetal brain. Infection of immature neural stem cells by invading microglia may occur in the early stages of pregnancy, before angiogenesis in the brain rudiments. Our data are also consistent with ZIKV and DENV affecting the integrity of the blood–brain barrier, thus allowing infection of the brain later in life. Keywords: Zika; microglia; organoids; interferon; iPSen_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant AI100190)en_US
dc.publisherNational Academy of Sciences (U.S.)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/PNAS.1719266115en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourcePNASen_US
dc.titleHuman induced pluripotent stem cell-derived glial cells and neural progenitors display divergent responses to Zika and dengue infectionsen_US
dc.typeArticleen_US
dc.identifier.citationMuffat, Julien et al. “Human Induced Pluripotent Stem Cell-Derived Glial Cells and Neural Progenitors Display Divergent Responses to Zika and Dengue Infections.” Proceedings of the National Academy of Sciences 115, 27 (June 2018): 7117–7122 © 2018 National Academy of Sciencesen_US
dc.contributor.departmentInstitute for Medical Engineering and Scienceen_US
dc.contributor.departmentDavid H. Koch Institute for Integrative Cancer Research at MITen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorDurbin, Ann F
dc.contributor.mitauthorBosch, Irene
dc.contributor.mitauthorGehrke, Lee
dc.relation.journalProceedings of the National Academy of Sciencesen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2019-02-08T18:23:05Z
dspace.orderedauthorsMuffat, Julien; Li, Yun; Omer, Attya; Durbin, Ann; Bosch, Irene; Bakiasi, Grisilda; Richards, Edward; Meyer, Aaron; Gehrke, Lee; Jaenisch, Rudolfen_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0002-9387-8212
mit.licensePUBLISHER_POLICYen_US


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