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

Silva-Filho, J. L.; The Zika-Unicamp Network,; Oliveira, L. G.; Monteiro, L.; Parise, P. L.; Zanluqui, N. G.; Polonio, C. M.; Freitas, C. L.; Toledo-Teixeira, D. A.; Souza, W. M.; Bittencourt, N.; Amorim, M. R.; Forato, J.; Muraro, S. P.; Souza, G. F.; Martini, M. C.; Bispos-dos-Santos, K.; Judice, C. C.; Costa, M. L.; Angerami, R. N.; Freitas, A. R. R.; Resende, M. R.; Garcia, M. T.; Moretti, M. L.; Renia, L.; Ng, L. F.; Rothlin, C. V.; Costa, F. T.; Peron, J. P. S.; Proenca-Modena, J. L.

doi:10.1101/2021.01.27.428402

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bioRxiv · 10.1101/2021.01.27.428402

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

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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 remain unknown. Gas6 is a soluble TAM receptor ligand able to promote flavivirus internalization and downregulation of immune responses. Here we demonstrate high Gas6 levels in the serum of patients with neurological complications which correlated with downregulation of genes associated with the type I IFN responses as consequence of Socs1 upregulation. Gas6 gamma-carboxylation is essential for ZIKV replication in monocytes, the main source of this protein. Gas6 also facilitates ZIKV replication in adult immunocompetent mice enabled susceptibility to transplacental infection and congenital malformations. Our data thus 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.

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Silva-Filho, J. L., The Zika-Unicamp Network,, Oliveira, L. G., Monteiro, L., Parise, P. L., Zanluqui, N. G., Polonio, C. M., Freitas, C. L., Toledo-Teixeira, D. A., Souza, W. M., Bittencourt, N., Amorim, M. R., Forato, J., Muraro, S. P., Souza, G. F., Martini, M. C., Bispos-dos-Santos, K., Judice, C. C., Costa, M. L., Angerami, R. N., Freitas, A. R. R., Resende, M. R., Garcia, M. T., Moretti, M. L., Renia, L., Ng, L. F., Rothlin, C. V., Costa, F. T., Peron, J. P. S., Proenca-Modena, J. L.. 2021-01-28. Gas6 drives Zika virus-induced neurological complications in humans and congenital syndrome in immunocompetent mice. https://doi.org/10.1101/2021.01.27.428402

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