Hippo Signaling Pathway Has a Critical Role in Zika Virus Replication and in the Pathogenesis of Neuroinflammation

Zika virus (ZIKV) is a reemerging human pathogen that causes congenital abnormalities including microcephaly and eye disease. The cell/molecular basis of ZIKV and host interactions inducing ocular and neuronal pathogenesis are unclear. Here we noted that the Hippo/SWH signaling pathway, which controls organ size through progenitor cell proliferation and differentiation, is dysregulated following ZIKV infection. In human fetal retinal pigment epithelial (RPE) cells, there is an early induction of transcriptional co‐activator, YAP, which is later degraded with a corresponding activation of the TBK1‐IRF3 Type I interferon pathway. YAP/TAZ silencing results in reduced ZIKV replication, indicating a direct role of Hippo pathway in regulating ZIKV infection. Using an in vivo Ifnr1−/− knockout mice model, ZIKV infection was found to reduce YAP/TAZ protein levels while increasing pYAP Ser127 in the retina and brain. Hippo pathway is activated in major components of the blood‐brain barrier (BBB), incuding endothelial cells and astrocytes. In addition, our data shows AMPK signaling pathway’s role in regulating YAP/TAZ in ZIKV‐infected cells. Our data demonstrates ZIKV infection initiates a crosstalk among AMPK‐Hippo‐TBK1 pathways, which regulate antiviral and energy stress responses during oculo‐neuronal inflammation. Support or Funding Information This work was funded by California Institute for Regenerative Medicine (CIRM) Quest – Discovery Stage Research Projects Grant (DISC2‐10188) to V.A. at the University of California, Los Angeles.