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

2021; Elsevier BV; Volume: 97; Linguagem: Inglês

10.1016/j.bbi.2021.08.008

1090-2139

João Luiz Silva‐Filho, Lilian Gomes de Oliveira, Leticia Monteiro, Pierina Lorencini Parise, Nágela Ghabdan Zanluqui, Carolina Manganeli Polonio, Carla Longo de Freitas, Daniel A. Toledo-Teixeira, William Marciel de Souza, Najara Carneiro Bittencourt, Mariene R. Amorim, Julia Forato, Stéfanie Primon Muraro, Gabriela Fabiano de Souza, Matheus Cavalheiro Martini, Karina Bispo-dos-Santos, Aline Vieira, Carla C. Judice, Gláucia María Pastore, Eliana Amaral, Renato Passini, Helaine Maria Besteti Pires Mayer-Milanez, Carolina C. Ribeiro‐do‐Valle, Roseli Calil, João Renato Bennini, Giuliane Jesus Lajos, Albina Altemani, Marcos Tadeu Nolasco da Silva, Ana Carolina Coan, Maria Francisca Colella‐Santos, Andrea Paula Bruno von Zuben, Marco Aurélio Ramirez Vinolo, Clarice Weis Arns, Rodrigo Ramos Catharino, Maria Laura Costa, Rodrigo Nogueira Angerami, André Ricardo Ribas Freitas, Mariângela Ribeiro Resende, Márcia Teixeira Garcia, Maria Luíza Moretti, Laurent Rénia, Lisa F. P. Ng, Carla V. Rothlin, Fábio Trindade Maranhão Costa, Jean Pierre Schatzmann Peron, José Luiz Proença‐Módena,

Complement system in diseases

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.