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

[Display omitted] •ZIKV neurological patients have increased Gas6 levels compared to controls.•Monocytes are the main sources of Gas6 and production is increased by ZIKV.•Gas6 correlate with increased SOCS1 expression suppressing type I interferon response.•GLA domain carboxylation of Gas6 is essent...

Full description

Saved in:
Bibliographic Details
Published in:Brain, behavior, and immunity behavior, and immunity, 2021-10, Vol.97, p.260-274
Main Authors: Silva-Filho, Joao Luiz, de Oliveira, Lilian G., Monteiro, Leticia, Parise, Pierina L., Zanluqui, Nagela G., Polonio, Carolina M., de Freitas, Carla L., Toledo-Teixeira, Daniel A., de Souza, William M., Bittencourt, Najara, Amorim, Mariene R., Forato, Julia, Muraro, Stéfanie P., de Souza, Gabriela F., Martini, Matheus C., Bispo-dos-Santos, Karina, Vieira, Aline, Judice, Carla C., Pastore, Glaucia M., Amaral, Eliana, Passini Junior, Renato, Mayer-Milanez, Helaine M.B.P., Ribeiro-do-Valle, Carolina C., Calil, Roseli, Renato Bennini Junior, João, Lajos, Giuliane J., Altemani, Albina, Nolasco da Silva, Marcos T., Carolina Coan, Ana, Francisca Colella-Santos, Maria, von Zuben, Andrea P.B., Vinolo, Marco Aurélio R., Arns, Clarice Weis, Catharino, Rodrigo Ramos, Costa, Maria Laura, Angerami, Rodrigo N., Freitas, André R.R., Resende, Mariangela R., Garcia, Márcia T., Luiza Moretti, Maria, Renia, Laurent, Ng, Lisa F.P., Rothlin, Carla V., Costa, Fabio T.M., Peron, Jean Pierre Schatzmann, Proença-Modena, José Luiz
Format: Article
Language:English
Subjects:
Congenital infection
Socs1
TAM receptors
Type I Interferon
Zika virus
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] •ZIKV neurological patients have increased Gas6 levels compared to controls.•Monocytes are the main sources of Gas6 and production is increased by ZIKV.•Gas6 correlate with increased SOCS1 expression suppressing type I interferon response.•GLA domain carboxylation of Gas6 is essential for ZIKV attachment to cell receptors.•ZIKV + rGas6 facilitates invasion and replication in placenta and mice fetal tissue. 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.
ISSN:0889-1591
1090-2139
DOI:10.1016/j.bbi.2021.08.008