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

Agradecimentos: 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 Extens˜ao (FAEPEX) supported M.R.A., grant number 208/17. J.L.P.-M. was supported by CNPq grant number 305628/2020-8 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 FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ Fechado