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

Harry Bulstrode; Gemma C Girdler; Tannia Gracia; Alexander Aivazidis; Ilias Moutsopoulos; Adam M H Young; John Hancock; Xiaoling He; Katherine Ridley; Zhaoyang Xu; John H Stockley; John Finlay; Clement Hallou; Teodoro Fajardo; Daniel M Fountain; Stijn van Dongen; Alexis Joannides; Robert Morris; Richard Mair; Colin Watts; Thomas Santarius; Stephen J Price; Peter J A Hutchinson; Emma J Hodson; Steven M Pollard; Irina Mohorianu; Roger A Barker; Trevor R Sweeney; Omer Bayraktar; Fanni Gergely; David H Rowitch

doi:10.1016/j.neuron.2022.09.002

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

Neuron. 2022 Dec 7;110(23):3936-3951.e10. doi: 10.1016/j.neuron.2022.09.002. Epub 2022 Sep 28.

Authors

Harry Bulstrode¹, Gemma C Girdler², Tannia Gracia³, Alexander Aivazidis⁴, Ilias Moutsopoulos⁵, Adam M H Young², John Hancock³, Xiaoling He⁵, Katherine Ridley⁶, Zhaoyang Xu⁶, John H Stockley⁶, John Finlay⁶, Clement Hallou⁶, Teodoro Fajardo⁷, Daniel M Fountain⁸, Stijn van Dongen⁴, Alexis Joannides⁹, Robert Morris⁹, Richard Mair⁹, Colin Watts¹⁰, Thomas Santarius⁹, Stephen J Price⁹, Peter J A Hutchinson⁹, Emma J Hodson¹¹, Steven M Pollard¹², Irina Mohorianu⁵, Roger A Barker⁵, Trevor R Sweeney¹³, Omer Bayraktar⁴, Fanni Gergely¹⁴, David H Rowitch¹⁵

Affiliations

¹ Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK; Division of Academic Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK. Electronic address: hb252@cam.ac.uk.
² Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK; Division of Academic Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK.
³ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
⁴ Wellcome Sanger Institute, Hinxton CB10 1SA, UK.
⁵ Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK.
⁶ Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK; Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK.
⁷ Department of Virology, University of Cambridge, Cambridge CB2 0QQ, UK; Department of Virology, Royal London Hospital, Barts Health NHS Trust, London E1 2ES, UK.
⁸ Manchester Centre for Clinical Neurosciences, Manchester M6 8HD, UK.
⁹ Division of Academic Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK.
¹⁰ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2SY, UK.
¹¹ Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge CB2 0QQ, UK.
¹² Centre for Regenerative Medicine and Cancer Research UK Edinburgh Centre, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh EH16 4UU, UK.
¹³ Department of Virology, University of Cambridge, Cambridge CB2 0QQ, UK; The Pirbright Institute, Guildford, Surrey GU24 0NF, UK.
¹⁴ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK. Electronic address: fanni.gergely@bioch.ox.ac.uk.
¹⁵ Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK; Wellcome Sanger Institute, Hinxton CB10 1SA, UK; Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK. Electronic address: dhr25@medschl.cam.ac.uk.

Abstract

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.

Keywords: GBM; Zika; flavivirus; glioblastoma; interferon; macrophage; microglia; myeloid; neural; oncolytic.

MeSH terms

Humans
Interferons
Myeloid Cells
Stem Cells
Zika Virus Infection*
Zika Virus*

Substances

Interferons

Abstract

MeSH terms

Substances

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