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 Amaral; Renato 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

doi:10.1016/j.bbi.2021.08.008

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

Microbiology And Immunology

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	260-274
Number of pages	15
Journal	Brain, Behavior, and Immunity
Volume	97
DOIs	https://doi.org/10.1016/j.bbi.2021.08.008
State	Published - 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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10.1016/j.bbi.2021.08.008

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Silva-Filho, J. L., de Oliveira, L. G., Monteiro, L., Parise, P. L., Zanluqui, N. G., Polonio, C. M., de Freitas, C. L., Toledo-Teixeira, D. A., de Souza, W. M., Bittencourt, N., Amorim, M. R., Forato, J., Muraro, S. P., de Souza, G. F., Martini, M. C., Bispo-dos-Santos, K., Vieira, A., Judice, C. C., Pastore, G. M., ... Proença-Modena, J. L. (2021). Gas6 drives Zika virus-induced neurological complications in humans and congenital syndrome in immunocompetent mice. Brain, Behavior, and Immunity, 97, 260-274. https://doi.org/10.1016/j.bbi.2021.08.008

Silva-Filho, JL, de Oliveira, LG, Monteiro, L, Parise, PL, Zanluqui, NG, Polonio, CM, de Freitas, CL, Toledo-Teixeira, DA, de Souza, WM, Bittencourt, N, Amorim, MR, Forato, J, Muraro, SP, de Souza, GF, Martini, MC, Bispo-dos-Santos, K, Vieira, A, Judice, CC, Pastore, GM, Amaral, E, Passini Junior, R, Mayer-Milanez, HMBP, Ribeiro-do-Valle, CC, Calil, R, Renato Bennini Junior, J, Lajos, GJ, Altemani, A, Nolasco da Silva, MT, Carolina Coan, A, Francisca Colella-Santos, M, von Zuben, APB, Vinolo, MAR, Arns, CW, Catharino, RR, Costa, ML, Angerami, RN, Freitas, ARR, Resende, MR, Garcia, MT, Luiza Moretti, M, Renia, L, Ng, LFP, Rothlin, CV, Costa, FTM, Peron, JPS & Proença-Modena, JL 2021, 'Gas6 drives Zika virus-induced neurological complications in humans and congenital syndrome in immunocompetent mice', Brain, Behavior, and Immunity, vol. 97, pp. 260-274. https://doi.org/10.1016/j.bbi.2021.08.008

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title = "Gas6 drives Zika virus-induced neurological complications in humans and congenital syndrome in immunocompetent mice",

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.",

keywords = "Congenital infection, Socs1, TAM receptors, Type I Interferon, Zika virus",

author = "Silva-Filho, {Joao Luiz} and {de Oliveira}, {Lilian G.} and Leticia Monteiro and Parise, {Pierina L.} and Zanluqui, {Nagela G.} and Polonio, {Carolina M.} and {de Freitas}, {Carla L.} and Toledo-Teixeira, {Daniel A.} and {de Souza}, {William M.} and Najara Bittencourt and Amorim, {Mariene R.} and Julia Forato and Muraro, {St{\'e}fanie P.} and {de Souza}, {Gabriela F.} and Martini, {Matheus C.} and Karina Bispo-dos-Santos and Aline Vieira and Judice, {Carla C.} and Pastore, {Glaucia M.} and Eliana Amaral and {Passini Junior}, Renato and Mayer-Milanez, {Helaine M.B.P.} and Ribeiro-do-Valle, {Carolina C.} and Roseli Calil and {Renato Bennini Junior}, Jo{\~a}o and Lajos, {Giuliane J.} and Albina Altemani and {Nolasco da Silva}, {Marcos T.} and {Carolina Coan}, Ana and {Francisca Colella-Santos}, Maria and {von Zuben}, {Andrea P.B.} and Vinolo, {Marco Aur{\'e}lio R.} and Arns, {Clarice Weis} and Catharino, {Rodrigo Ramos} and Costa, {Maria Laura} and Angerami, {Rodrigo N.} and Freitas, {Andr{\'e} R.R.} and Resende, {Mariangela R.} and Garcia, {M{\'a}rcia T.} and {Luiza Moretti}, Maria and Laurent Renia and Ng, {Lisa F.P.} and Rothlin, {Carla V.} and Costa, {Fabio T.M.} and Peron, {Jean Pierre Schatzmann} and Proen{\c c}a-Modena, {Jos{\'e} Luiz}",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = oct,

doi = "10.1016/j.bbi.2021.08.008",

language = "English (US)",

volume = "97",

pages = "260--274",

journal = "Brain, Behavior, and Immunity",

issn = "0889-1591",

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TY - JOUR

T1 - Gas6 drives Zika virus-induced neurological complications in humans and congenital syndrome in immunocompetent mice

AU - Silva-Filho, Joao Luiz

AU - de Oliveira, Lilian G.

AU - Monteiro, Leticia

AU - Parise, Pierina L.

AU - Zanluqui, Nagela G.

AU - Polonio, Carolina M.

AU - de Freitas, Carla L.

AU - Toledo-Teixeira, Daniel A.

AU - de Souza, William M.

AU - Bittencourt, Najara

AU - Amorim, Mariene R.

AU - Forato, Julia

AU - Muraro, Stéfanie P.

AU - de Souza, Gabriela F.

AU - Martini, Matheus C.

AU - Bispo-dos-Santos, Karina

AU - Vieira, Aline

AU - Judice, Carla C.

AU - Pastore, Glaucia M.

AU - Amaral, Eliana

AU - Passini Junior, Renato

AU - Mayer-Milanez, Helaine M.B.P.

AU - Ribeiro-do-Valle, Carolina C.

AU - Calil, Roseli

AU - Renato Bennini Junior, João

AU - Lajos, Giuliane J.

AU - Altemani, Albina

AU - Nolasco da Silva, Marcos T.

AU - Carolina Coan, Ana

AU - Francisca Colella-Santos, Maria

AU - von Zuben, Andrea P.B.

AU - Vinolo, Marco Aurélio R.

AU - Arns, Clarice Weis

AU - Catharino, Rodrigo Ramos

AU - Costa, Maria Laura

AU - Angerami, Rodrigo N.

AU - Freitas, André R.R.

AU - Resende, Mariangela R.

AU - Garcia, Márcia T.

AU - Luiza Moretti, Maria

AU - Renia, Laurent

AU - Ng, Lisa F.P.

AU - Rothlin, Carla V.

AU - Costa, Fabio T.M.

AU - Peron, Jean Pierre Schatzmann

AU - Proença-Modena, José Luiz

PY - 2021/10

Y1 - 2021/10

N2 - 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.

AB - 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.

KW - Congenital infection

KW - Socs1

KW - TAM receptors

KW - Type I Interferon

KW - Zika virus

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UR - http://www.scopus.com/inward/citedby.url?scp=85112833482&partnerID=8YFLogxK

U2 - 10.1016/j.bbi.2021.08.008

DO - 10.1016/j.bbi.2021.08.008

M3 - Article

C2 - 34390806

AN - SCOPUS:85112833482

SN - 0889-1591

VL - 97

SP - 260

EP - 274

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

ER -

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

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Keywords

ASJC Scopus subject areas

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