Myeloid cell interferon secretion restricts Zika flavivirus infection of developing and malignant human neural progenitor cells

Zika virus (ZIKV) can infect human developing brain (HDB) progenitors resulting in epidemic microcephaly, whereas analogous cellular tropism offers treatment potential for the adult brain cancer, glioblastoma (GBM). We compared productive ZIKV infection in HDB and GBM primary tissue explants that bo...

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Published in:Neuron (Cambridge, Mass.) Mass.), 2022-12, Vol.110 (23), p.3936-3951.e10
Main Authors: Bulstrode, Harry, Girdler, Gemma C., Gracia, Tannia, Aivazidis, Alexander, Moutsopoulos, Ilias, Young, Adam M.H., Hancock, John, He, Xiaoling, Ridley, Katherine, Xu, Zhaoyang, Stockley, John H., Finlay, John, Hallou, Clement, Fajardo, Teodoro, Fountain, Daniel M., van Dongen, Stijn, Joannides, Alexis, Morris, Robert, Mair, Richard, Watts, Colin, Santarius, Thomas, Price, Stephen J., Hutchinson, Peter J.A., Hodson, Emma J., Pollard, Steven M., Mohorianu, Irina, Barker, Roger A., Sweeney, Trevor R., Bayraktar, Omer, Gergely, Fanni, Rowitch, David H.
Format: Article
Language:English
Subjects:
flavivirus
GBM
glioblastoma
Humans
interferon
Interferons
macrophage
microglia
myeloid
Myeloid Cells
neural
oncolytic
Stem Cells
Zika
Zika Virus
Zika Virus Infection
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Summary:Zika virus (ZIKV) can infect human developing brain (HDB) progenitors resulting in epidemic microcephaly, whereas analogous cellular tropism offers treatment potential for the adult brain cancer, glioblastoma (GBM). We compared productive ZIKV infection in HDB and GBM primary tissue explants that both contain SOX2+ neural progenitors. Strikingly, although the HDB proved uniformly vulnerable to ZIKV infection, GBM was more refractory, and this correlated with an innate immune expression signature. Indeed, GBM-derived CD11b+ microglia/macrophages were necessary and sufficient to protect progenitors against ZIKV infection in a non-cell autonomous manner. Using SOX2+ GBM cell lines, we found that CD11b+-conditioned medium containing type 1 interferon beta (IFNβ) promoted progenitor resistance to ZIKV, whereas inhibition of JAK1/2 signaling restored productive infection. Additionally, CD11b+ conditioned medium, and IFNβ treatment rendered HDB progenitor lines and explants refractory to ZIKV. These findings provide insight into neuroprotection for HDB progenitors as well as enhanced GBM oncolytic therapies. •Glioblastoma is refractory to Zika virus (ZIKV) compared with human developing brain•Myeloid cell interferon secretion restricts ZIKV infection in glioblastoma (GBM)•Clinical inhibitors of JAK/STAT signaling enhance ZIKV infection in GBM cells•Myeloid cell coculture or interferon protects the developing brain from ZIKV infection Zika virus (ZIKV) infects parallel neural progenitor cell populations in the developing brain and in glioblastoma brain tumors. Bulstrode et al. demonstrate that interferon secretion by human brain myeloid cells can render each neural progenitor population refractory to ZIKV infection, with important implications for neuroprotection and viral oncolysis.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2022.09.002