Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin αvβ5 Axis.

Abstract

Zika virus (ZIKV) causes microcephaly by killing neural precursor cells (NPCs) and other brain cells. ZIKV also displays therapeutic oncolytic activity against glioblastoma (GBM) stem cells (GSCs). Here we demonstrate that ZIKV preferentially infected and killed GSCs and stem-like cells in medulloblastoma and ependymoma in a SOX2-dependent manner. Targeting SOX2 severely attenuated ZIKV infection, in contrast to AXL. As mechanisms of SOX2-mediated ZIKV infection, we identified inverse expression of antiviral interferon response genes (ISGs) and positive correlation with integrin αv (ITGAV). ZIKV infection was disrupted by genetic targeting of ITGAV or its binding partner ITGB5 and by an antibody specific for integrin αvβ5. ZIKV selectively eliminated GSCs from species-matched human mature cerebral organoids and GBM surgical specimens, which was reversed by integrin αvβ5 inhibition. Collectively, our studies identify integrin αvβ5 as a functional cancer stem cell marker essential for GBM maintenance and ZIKV infection, providing potential brain tumor therapy.

• Authors: Zhe Zhu, Pinar Mesci, Jean A Bernatchez, Ryan C Gimple, Xiuxing Wang, Simon T Schafer, Hiromi I Wettersten, Sungjun Beck, Alex E Clark, Qiulian Wu, Briana C Prager, Leo J Y Kim, Rekha Dhanwani, Sonia Sharma, Alexandra Garancher, Sara M Weis, Stephen C Mack, Priscilla D Negraes, Cleber A Trujillo, Luiz O Penalva, Jing Feng, Zhou Lan, Rong Zhang, Alex W Wessel, Sanjay Dhawan, Michael S Diamond, Clark C Chen, Robert J Wechsler-Reya, Fred H Gage, Hongzhen Hu, Jair L Siqueira-Neto, Alysson R Muotri, David A Cheresh, Jeremy N Rich
• Journal: Cell stem cell (Cell Stem Cell) Vol. 26 Issue 2 Pg. 187-204.e10 (02 06 2020) ISSN: 1875-9777 [Electronic] United States
• PMID: 31956038 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Receptors, Vitronectin
• SOX2 protein, human
• SOXB1 Transcription Factors
• integrin alphaVbeta5

Topics

• Glioblastoma
• Humans
• Neural Stem Cells
• Receptors, Vitronectin
• SOXB1 Transcription Factors (genetics)
• Zika Virus
• Zika Virus Infection