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

Joao Luiz Silva-Filho, Lilian G. de Oliveira, Leticia Monteiro, Pierina L. Parise, Nagela G. Zanluqui, Carolina M. Polonio, Carla L. de Freitas, Daniel A. Toledo-Teixeira, William M. de Souza, Najara Bittencourt, Mariene R. Amorim, Julia Forato, Stéfanie P. Muraro, Gabriela F. de Souza, Matheus C. Martini, Karina Bispo-dos-Santos, Aline Vieira, Carla C. Judice, Glaucia M. Pastore, Eliana AmaralRenato Passini Junior, Helaine M.B.P. Mayer-Milanez, Carolina C. Ribeiro-do-Valle, Roseli Calil, João Renato Bennini Junior, Giuliane J. Lajos, Albina Altemani, Marcos T. Nolasco da Silva, Ana Carolina Coan, Maria Francisca Colella-Santos, Andrea P.B. von Zuben, Marco Aurélio R. Vinolo, Clarice Weis Arns, Rodrigo Ramos Catharino, Maria Laura Costa, Rodrigo N. Angerami, André R.R. Freitas, Mariangela R. Resende, Márcia T. Garcia, Maria Luiza Moretti, Laurent Renia, Lisa F.P. Ng, Carla V. Rothlin, Fabio T.M. Costa, Jean Pierre Schatzmann Peron, José Luiz Proença-Modena

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)260-274
Number of pages15
JournalBrain, Behavior, and Immunity
Volume97
DOIs
StatePublished - Oct 2021

Keywords

  • Congenital infection
  • Socs1
  • TAM receptors
  • Type I Interferon
  • Zika virus

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

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