SREBP2-dependent lipid gene transcription enhances the infection of human dendritic cells by Zika virus
Emilie Branche, Ying-Ting Wang, Karla M. Viramontes, Joan M. Valls Cuevas, Jialei Xie, Fernanda Ana‐Sosa‐Batiz, Norazizah Shafee, Sascha H. Duttke, Rachel E. McMillan, Alex E. Clark, Michael N. Nguyen, Aaron F. Garretson, Jan J. Crames, Nathan J. Spann, Zhe Zhu, Jeremy N. Rich, Deborah H. Spector, Christopher Benner, Sujan Shresta, Aaron F. Carlin
Abstract
The emergence of Zika virus (ZIKV) as a global health threat has highlighted the unmet need for ZIKV-specific vaccines and antiviral treatments. ZIKV infects dendritic cells (DC), which have pivotal functions in activating innate and adaptive antiviral responses; however, the mechanisms by which DC function is subverted to establish ZIKV infection are unclear. Here we develop a genomics profiling method that enables discrete analysis of ZIKV-infected versus neighboring, uninfected primary human DCs to increase the sensitivity and specificity with which ZIKV-modulated pathways can be identified. The results show that ZIKV infection specifically increases the expression of genes enriched for lipid metabolism-related functions. ZIKV infection also increases the recruitment of sterol regulatory element-binding protein (SREBP) transcription factors to lipid gene promoters, while pharmacologic inhibition or genetic silencing of SREBP2 suppresses ZIKV infection of DCs. Our data thus identify SREBP2-activated transcription as a mechanism for promoting ZIKV infection amenable to therapeutic targeting.