Gas6 drives Zika virus-induced neurological complications in humans and congenital syndrome in immunocompetent mice

Brain Behav Immun. 2021 Oct:97:260-274. doi: 10.1016/j.bbi.2021.08.008. Epub 2021 Aug 11.

Abstract

Zika virus (ZIKV) has the ability to cross placental and brain barriers, causing congenital malformations in neonates and neurological disorders in adults. However, the pathogenic mechanisms of ZIKV-induced neurological complications in adults and congenital malformations are still not fully understood. Gas6 is a soluble TAM receptor ligand able to promote flavivirus internalization and downregulation of immune responses. Here we demonstrate that there is a correlation between ZIKV neurological complications with higher Gas6 levels and the downregulation of genes associated with anti-viral response, as type I IFN due to Socs1 upregulation. Also, Gas6 gamma-carboxylation is essential for ZIKV invasion and replication in monocytes, the main source of this protein, which was inhibited by warfarin. Conversely, Gas6 facilitates ZIKV replication in adult immunocompetent mice and enabled susceptibility to transplacental infection. Our data indicate that ZIKV promotes the upregulation of its ligand Gas6, which contributes to viral infectivity and drives the development of severe adverse outcomes during ZIKV infection.

Keywords: Congenital infection; Socs1; TAM receptors; Type I Interferon; Zika virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Humans
  • Mice
  • Nervous System Diseases*
  • Placenta
  • Pregnancy
  • Virus Replication
  • Zika Virus Infection* / complications
  • Zika Virus*