The Myeloid Cell Secretome Regulates Zika Flavivirus Infection of Developing and Malignant Human Neural Progenitor Cells

Abstract

Epidemic Zika Virus (ZIKV) infection targeting human developing brain (HDB) stem cells has resulted in devastating tissue damage and microcephaly, whereas analogous neural stem cell tropism offers treatment potential in the lethal adult brain cancer, glioblastoma (GBM). We compared ZIKV infection in primary HDB and GBM tissue that both contain prominent SOX2+ neural progenitor cell fractions. Strikingly, whereas HDB proved uniformly susceptible to ZIKV, GBM tissue was significantly more resistant. RNA sequencing revealed that relative ZIKV resistance in GBM versus HDB strongly correlated with a microenvironment-associated innate immune expression signature, rather than cell-intrinsic differences in target SOX2+ cells. Indeed, we found that isolated GBM tumour microenvironment CD11-positive microglia and macrophages were necessary and sufficient to drive progenitor cell resistance against ZIKV in a non-cell autonomous manner. As these properties were conferred by GBM myeloid cell conditioned medium, we tested secreted candidate cytokines. This identified microenvironment type 1 interferon secretion as a key regulator of GBM progenitor cell resistance to ZIKV, and that inhibition of downstream JAK1/2 signaling enhanced infection and consequent viral oncolysis. Conversely, we found, addition of microglia or derived conditioned medium, promoted Zika resistance of HDB SOX2+ progenitor cells.  These findings indicate that the myeloid cell secretome regulates ZIKV infection of developing and malignant human neural progenitor cells, providing insight into both neuroprotection and oncolytic therapy.

Funding Information: Cancer Research UK Pioneer Award A24423 (HB) Wellcome Career Development Fellowship 223011/Z/21/Z (HB) Cancer Research UK C14303/A17197 and A24455 (FG) Dr Miriam and Sheldon G Adelson Medical Research Foundation (DHR) European Research Council Advanced Grant, GA no 789054 (DHR) Wellcome Trust Investigator Award 88114 (DHR) Wellcome Trust/Royal Society Sir Henry Dale Fellowship award 02471/Z/16/Z (TRS) Cancer Research UKA21922 (GCGR lines: SP) NIHR Cambridge Biomedical Research Centre (BRC-1215-20014, DHR).

Declaration of Interests: The authors declare no competing interests.

Ethics Approval Statement: GCGR cell lines were generated and supplied with ethical approval from the NHS Health Research Authority (East of Scotland Research Ethics Service, REC reference 15/ES/0094). The acquisition of HDB tissue was undertaken by Xiaoling He under provisions of REC 96/085 (Principal Investigator Roger Barker). Patient GBM tissue was obtained with informed consent under REC 18/WM/0094 (Principal Investigator Harry Bulstrode), NRES Committee West Midlands and processed immediately following resection. Both patient GBM tissue and HDB tissue were processed under the provisions of REC 18/WM/0094 and HTA regulations.

Keywords: Glioblastoma, GBM, neural, Zika, flavivirus, oncolytic, microglia, macrophage, myeloid, interferon, cytokine