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

5 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
Pages (from-to)260-274
Number of pages15
JournalBrain, Behavior, and Immunity
Volume97
DOIs
StatePublished - Oct 2021

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.

Funding

This study was financially supported by the São Paulo Research Foundation (FAPESP 2016/00194-8; 2017/26170-0 and 2017/22054-1); Biomedical Research Council (BMRC; core research grants provided to the Singapore Immunology Network); the BMRC A*STAR-led Zika Virus Consortium Fund (project 15/1/82/27/001); the Agency for Science, Technology and Research (A*STAR), Singapore. J.L.S.F., L.G.O., L.M., P.L.P., N.G.Z., C.M.P., D.A.T.-T., W.M.S., N.B., J.F., S.P.M., G.F.S. and K.B.-d.-S., received scholarship from FAPESP, grant numbers 2016/12855-9; 2016/21259-0; 2018/13866-0; 2017/02402-0, 2016/07371-2; 2017/11828-0; 2017/26908-0, 2017/22062-9, 2018/13645-3, 2020/02159-0 and 2020/02448-2, respectively. National Council for Scientific and Technological Development (CNPq) supported D.A.T.-T. and M.C.M., grant numbers 141844/2019-1 and 421724/2017-0. Fundo de Apoio ao Ensino, Pesquisa e Extensão (FAEPEX) supported M.R.A., grant number 208/17. J.L.P.-M. was supported by CNPq grant number 305628/2020-8. We thank the study participants and healthy volunteers for their participation and the clinical staffs from University of Campinas Hospitals and other hospitals of this city for assistance in patient enrolment and healthcare, blood sample preparation, study coordination, and data entry. We thank the staff of the Life Sciences Core Facility (LaCTAD) from Unicamp for the High-throughput sequencing. Financial support. This study was financially supported by the S?o Paulo Research Foundation (FAPESP 2016/00194-8; 2017/26170-0 and 2017/22054-1); Biomedical Research Council (BMRC; core research grants provided to the Singapore Immunology Network); the BMRC A*STAR-led Zika Virus Consortium Fund (project 15/1/82/27/001); the Agency for Science, Technology and Research (A*STAR), Singapore. J.L.S.F. L.G.O. L.M. P.L.P. N.G.Z. C.M.P. D.A.T.-T. W.M.S. N.B. J.F. S.P.M. G.F.S. and K.B.-d.-S. received scholarship from FAPESP, grant numbers 2016/12855-9; 2016/21259-0; 2018/13866-0; 2017/02402-0, 2016/07371-2; 2017/11828-0; 2017/26908-0, 2017/22062-9, 2018/13645-3, 2020/02159-0 and 2020/02448-2, respectively. National Council for Scientific and Technological Development (CNPq) supported D.A.T.-T. and M.C.M. grant numbers 141844/2019-1 and 421724/2017-0. Fundo de Apoio ao Ensino, Pesquisa e Extens?o (FAEPEX) supported M.R.A. grant number 208/17. J.L.P.-M. was supported by CNPq grant number 305628/2020-8. Disclaimer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

FundersFunder number
FAEPEX-UNICAMP305628/2020-8, 208/17
Fundo de Apoio ao Ensino, Pesquisa e Extens?o
Fundo de Apoio ao Ensino, Pesquisa e Extensão
Agency for Science Technology and Research2017/26908-0, 2017/02402-0, 2020/02448-2, 2020/02159-0, 2018/13866-0, 2016/07371-2, 2017/22062-9, 2016/21259-0, 2018/13645-3, 2016/12855-9, 2017/11828-0
Agency for Science Technology and Research
Fundação de Amparo à Pesquisa do Estado de São Paulo2016/00194-8, 2017/26170-0, 2017/22054-1
Fundação de Amparo à Pesquisa do Estado de São Paulo
Conselho Nacional de Desenvolvimento Científico e Tecnológico141844/2019-1, 421724/2017-0
Conselho Nacional de Desenvolvimento Científico e Tecnológico
College Research Council of the College of Veterinary Medicine and Biomedical Sciences15/1/82/27/001
College Research Council of the College of Veterinary Medicine and Biomedical Sciences

    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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