Western Zika Virus in Human Fetal Neural Progenitors Persists Long Term with Partial Cytopathic and Limited Immunogenic Effects

• Published in: Cell reports (Cambridge) 2016-06, Vol.15 (11), p.2315-2322
• Main Authors: Hanners, Natasha W., Eitson, Jennifer L., Usui, Noriyoshi, Richardson, R. Blake, Wexler, Eric M., Konopka, Genevieve, Schoggins, John W.
• Format: Article
• Language: English
• Subjects: Cell Line; Cytopathogenic Effect, Viral - immunology; Fetus - pathology; Humans; Neural Stem Cells - immunology; Neural Stem Cells - virology; Time Factors; Virus Replication; Zika virus; Zika Virus - immunology; Zika Virus - isolation & purification; Zika Virus - physiology; Zika Virus - ultrastructure; Zika Virus Infection - immunology; Zika Virus Infection - virology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.05.075

The recent Zika virus (ZIKV) outbreak in the Western hemisphere is associated with severe pathology in newborns, including microcephaly and brain damage. The mechanisms underlying these outcomes are under intense investigation. Here, we show that a 2015 ZIKV isolate replicates in multiple cell types, including primary human fetal neural progenitors (hNPs). In immortalized cells, ZIKV is cytopathic and grossly rearranges endoplasmic reticulum membranes similar to other flaviviruses. In hNPs, ZIKV infection has a partial cytopathic phase characterized by cell rounding, pyknosis, and activation of caspase 3. Despite notable cell death, ZIKV did not activate a cytokine response in hNPs. This lack of cell intrinsic immunity to ZIKV is consistent with our observation that virus replication persists in hNPs for at least 28 days. These findings, supported by published fetal neuropathology, establish a proof-of-concept that neural progenitors in the developing human fetus can be direct targets of detrimental ZIKV-induced pathology. [Display omitted] •A 2015 ZIKV isolate replicates in human fetal neural progenitors•ZIKV in fetal neural progenitors is partially cytopathic and persists for weeks•ZIKV has limited immunogenic effects in fetal neural progenitors Hanners et al. establish a cell-culture model of a 2015 ZIKV isolate in primary human fetal neural progenitors. They show that ZIKV infection kills a subset of fetal neural progenitors with limited activation of inflammatory or immune responses. In the surviving neural progenitors, ZIKV replication persists for many weeks, mirroring fetal neuropathological findings in vivo.