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

Author(s):Show less -

Silva-Filho, Joao Luiz ^[1] ; de Oliveira, Lilian G. ^[2] ; Monteiro, Leticia ^[1] ; Parise, Pierina L. ^[3] ; Zanluqui, Nagela G. ^[2] ; Polonio, Carolina M. ^[2] ; de Freitas, Carla L. ^[2] ; Toledo-Teixeira, Daniel A. ^[3] ; de Souza, William M. ^{[4, 5]} ; Bittencourt, Najara ^[1] ; Amorim, Mariene R. ^[3] ; Forato, Julia ^[3] ; Muraro, Stefanie P. ^[3] ; de Souza, Gabriela F. ^[3] ; Martini, Matheus C. ^[3] ; Bispo-dos-Santos, Karina ^[3] ; Vieira, Aline ^[3] ; Judice, Carla C. ^[1] ; Pastore, Glaucia M. ^[6] ; Amaral, Eliana ^[7] ; Passini Junior, Renato ^[7] ; Mayer-Milanez, Helaine M. B. P. ^[7] ; Ribeiro-do-Valle, Carolina C. ^[7] ; Calil, Roseli ^[7] ; Bennini Junior, Joao Renato ^[7] ; Lajos, Giuliane J. ^[7] ; Altemani, Albina ^[8] ; Nolasco da Silva, Marcos T. ^[9] ; Coan, Ana Carolina ^[10] ; Colella-Santos, Maria Francisca ^[11] ; von Zuben, Andrea P. B. ^[12] ; Vinolo, Marco Aurelio R. ^[13] ; Arns, Clarice Weis ^[13] ; Catharino, Rodrigo Ramos ^[14] ; Costa, Maria Laura ^[7] ; Angerami, Rodrigo N. ^{[15, 12]} ; Freitas, Andre R. R. ^[12] ; Resende, Mariangela R. ^[15] ; Garcia, Marcia T. ^[15] ; Moretti, Maria Luiza ^[15] ; Renia, Laurent ^{[16, 17]} ; Ng, Lisa F. P. ^{[16, 17]} ; Rothlin, V, Carla ; Costa, Fabio T. M. ^[1] ; Schatzmann Peron, Jean Pierre ^{[2, 18, 19]} ; Proenca-Modena, Jose Luiz ^{[20, 3]}

Affiliation:Show less -

^[1] Univ Estadual Campinas, Inst Biol, Dept Genet Evolut Microbiol & Immunol, Lab Trop Dis Prof Luiz Jacintho Silva, Campinas - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Neuroimmune Interact Lab, Sao Paulo - Brazil

^[3] Univ Estadual Campinas, Inst Biol, Dept Genet Evolut Microbiol & Immunol, Lab Emerging Viruses LEVE, Campinas - Brazil

^[4] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 - USA

^[5] Univ Sao Paulo, Virol Res Ctr, Ribeirao Preto Med Sch, Ribeirao Preto - Brazil

^[6] Univ Estadual Campinas, Fac Food Engn, Campinas, SP - Brazil

^[7] Univ Estadual Campinas, Sch Med Sci, Dept Obstet & Gynecol, Campinas - Brazil

^[8] Univ Estadual Campinas, Sch Med Sci, Dept Clin Pathol, Campinas - Brazil

^[9] Univ Estadual Campinas, Ctr Invest Pediat, Fac Med Sci, Pediat Immunol, Campinas, SP - Brazil

^[10] Univ Estadual Campinas, Dept Neurol, Sch Med Sci, Campinas, SP - Brazil

^[11] Univ Estadual Campinas, Dept Human Dev & Rehabil, Sch Med Sci, Campinas, SP - Brazil

^[12] Campinas Dept Publ Hlth Surveillance, Campinas - Brazil

^[13] Univ Estadual Campinas, Dept Genet Microbiol & Immunol, Inst Biol, Campinas, SP - Brazil

^[14] Univ Estadual Campinas, Sch Pharmaceut Sci, Campinas - Brazil

^[15] Univ Estadual Campinas, Sch Med Sci, Dept Internal Med, Campinas, SP - Brazil

^[16] Agcy Sci Technol & Res, Biopolis, Singapore Immunol Network, Singapore - Singapore

^[17] Agcy Sci Technol & Res, Biopolis, A Star Infect Dis Labs A ID Labs, Singapore - Singapore

^[18] Univ Sao Paulo, Sch Med, Immunopathol & Allergy Post Grad Program, Sao Paulo - Brazil

^[19] Univ Sao Paulo, Sci Platform Pasteur USP, Sao Paulo, SP - Brazil

^[20] Univ Estadual Campinas, Expt Med Res Cluster EMRC, BR-13083862 Campinas, SP - Brazil

• Document type: Journal article
• Source: BRAIN BEHAVIOR AND IMMUNITY; v. 97, p. 260-274, OCT 2021.
• Web of Science Citations: 1

Abstract

Zika virus (ZIKV) has the ability to cross placental and brain barriers, causing congenital malformations in ne-onates 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. (AU)

• FAPESP's process: 17/26908-0 - The role of IRF-5 in Oropouche virus pathogenesis and neurovirulence
• Grantee: Pierina Lorencini Parise
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 16/00194-8 - Pathogenesis and neurovirulence of emerging viruses in Brazil
• Grantee: José Luiz Proença Módena
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 20/02159-0 - Antiviral activity of AAK1 inhibitors against Oropouche infection
• Grantee: Karina Bispo dos Santos
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 16/21259-0 - The role of TAM receptors and their ligands, Gas6 and Pros 1 during infection by Zika virus in bone marrow-derived dendritic cells and macrophages of SJL and C57BL/6 mice
• Grantee: Lilian Gomes de Oliveira
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 18/13866-0 - Role of Gas6, ligand of TAM-type receptors, in the pathogenesis of Zika Virus infection in humans
• Grantee: Letícia Cristina Scarapicchia Monteiro
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 16/12855-9 - Mechanism of action of lipoxin in the protection against experimental cerebral malaria
• Grantee: João Luiz da Silva Filho
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/22062-9 - Arbovirus detection and characterization in Campinas
• Grantee: Julia Forato
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 17/26170-0 - Neuroimmunology in experimental models of Autoimmune Encephalomyelitis and Congenital Zika Syndrome: physiopathogenesis, susceptibility, cellular therapy, vaccination
• Grantee: Carolina Demarchi Munhoz
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/11828-0 - Evaluation of the microRNAs role in the immunopathogenesis of microcephaly caused by Zika virus in experimental models
• Grantee: Carolina Manganeli Polonio
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/02402-0 - The role of adaptive immune response in neuroinvasion by Oropouche and Zika virus
• Grantee: Daniel Augusto de Toledo Teixeira
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 20/02448-2 - The role of the presence of IRF-5 in dendritic cells, macrophages and B lymphocytes to control infection by the Oropouche virus in murine model
• Grantee: Camila Lopes Simeoni
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 18/13645-3 - The role of innate recognition pathways and type I and III interferons in the rupture of the placental barrier after OROV infection
• Grantee: Stefanie Primon Muraro
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/07371-2 - Characterization of the role of T CD8+ lymphocytes in Zika virus infection
• Grantee: Nagela Ghabdan Zanluqui
• Support Opportunities: Scholarships in Brazil - Doctorate