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

Aug 16, 2021

Contributor: 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

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

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.
Copyright © 2021. Published by Elsevier Inc.

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Joao Luiz Silva-Filho

Laboratory of Tropical Diseases Prof. Luiz Jacintho Silva, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.

Lilian G de Oliveira

Neuroimmune Interactions Laboratory, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil.

Leticia Monteiro

Laboratory of Tropical Diseases Prof. Luiz Jacintho Silva, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.

Pierina L Parise

Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.

Nagela G Zanluqui

Neuroimmune Interactions Laboratory, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil.

Carolina M Polonio

Neuroimmune Interactions Laboratory, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil.

Carla L de Freitas

Neuroimmune Interactions Laboratory, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil.

Daniel A Toledo-Teixeira

Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.

William M de Souza

Virology Research Center, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.

Najara Bittencourt

Laboratory of Tropical Diseases Prof. Luiz Jacintho Silva, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.

Mariene R Amorim

Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.

Julia Forato

Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.

Stéfanie P Muraro

Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.

Gabriela F de Souza

Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.

Matheus C Martini

Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.

Karina Bispo-Dos-Santos

Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.

Aline Vieira

Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.

Carla C Judice

Laboratory of Tropical Diseases Prof. Luiz Jacintho Silva, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.

Glaucia M Pastore

Faculty of Food Engineering, UNICAMP, Brazil.

Eliana Amaral

Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas, Campinas. Brazil.

Renato Passini Junior

Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas, Campinas. Brazil.

Helaine M B P Mayer-Milanez

Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas, Campinas. Brazil.

Carolina C Ribeiro-do-Valle

Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas, Campinas. Brazil.

Roseli Calil

Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas, Campinas. Brazil.

João Renato Bennini Junior

Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas, Campinas. Brazil.

Giuliane J Lajos

Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas, Campinas. Brazil.

Albina Altemani

Department of Clinical Pathology, School of Medical Sciences, University of Campinas, Campinas, Brazil.

Marcos T Nolasco da Silva

Pediatric Immunology, Center for Investigation in Pediatrics, Faculty of Medical Sciences, UNICAMP, Brazil.

Ana Carolina Coan

Department of Neurology, School of Medical Sciences, UNICAMP, Brazil.

Maria Francisca Colella-Santos

Department of Human Development and Rehabilitation, School of Medical Sciences, UNICAMP, Brazil.

Andrea P B von Zuben

Campinas Department of Public Health Surveillance, Campinas, Brazil.

Marco Aurélio R Vinolo

Department of Genetics, Microbiology and Immunology, Institute of Biology, UNICAMP, Brazil.

Clarice Weis Arns

Department of Genetics, Microbiology and Immunology, Institute of Biology, UNICAMP, Brazil.

Rodrigo Ramos Catharino

School of Pharmaceutical Sciences, UNICAMP, Campinas, Brazil.

Maria Laura Costa

Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas, Campinas. Brazil.

Rodrigo N Angerami

Campinas Department of Public Health Surveillance, Campinas, Brazil; Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil.

André R R Freitas

Campinas Department of Public Health Surveillance, Campinas, Brazil.

Mariangela R Resende

Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil.

Márcia T Garcia

Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil.

Maria Luiza Moretti

Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil.

Laurent Renia

A*STAR Infectious Diseases Labs (A* ID Labs), Agency for Science, Technology and Research, Biopolis, Singapore; Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Singapore.

Lisa F P Ng

Carla V Rothlin

Department of Immunobiology, Yale University, School of Medicine, New Haven, CT, United States.

Fabio T M Costa

Laboratory of Tropical Diseases Prof. Luiz Jacintho Silva, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil. Electronic address: costaftm@unicamp.br.

Jean Pierre Schatzmann Peron

Neuroimmune Interactions Laboratory, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil; Immunopathology and Allergy Post Graduate Program, School of Medicine, University of São Paulo, São Paulo, Brazil; Scientific Platform Pasteur-USP, University of São Paulo (USP), São Paulo, SP Brazil. Electronic address: jeanpierre@usp.br.

José Luiz Proença-Modena

Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil; Experimental Medicine Research Cluster (EMRC), University of Campinas, Campinas, SP 13083-862, Brazil. Electronic address: jlmodena@unicamp.br.

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

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