The Brazilian Zika virus strain causes birth defects in experimental models

Autor(es):Mostrar menos -

Cugola, Fernanda R. ^[1] ; Fernandes, Isabella R. ^{[1, 2]} ; Russo, Fabiele B. ^{[1, 3]} ; Freitas, Beatriz C. ^[2] ; Dias, Joao L. M. ^[1] ; Guimaraes, Katia P. ^[1] ; Benazzato, Cecilia ^[1] ; Almeida, Nathalia ^[1] ; Pignatari, Graciela C. ^{[1, 3]} ; Romero, Sarah ^[2] ; Polonio, Carolina M. ^[4] ; Cunha, Isabela ^[4] ; Freitas, Carla L. ^[4] ; Brandao, Wesley N. ^[4] ; Rossato, Cristiano ^[4] ; Andrade, David G. ^[4] ; Faria, Daniele de P. ^[5] ; Garcez, Alexandre T. ^[5] ; Buchpigel, Carlos A. ^[5] ; Braconi, Carla T. ^[6] ; Mendes, Erica ^[6] ; Sall, Amadou A. ^[7] ; Zanotto, Paolo M. de A. ^[6] ; Peron, Jean Pierre S. ^[4] ; Muotri, Alysson R. ^[2] ; Beltrao-Braga, Patricia C. B. ^{[8, 1]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Dept Surg, Stem Cell Lab, BR-05508270 Sao Paulo - Brazil

^[2] Univ Calif San Diego, Dept Cellular & Mol Med, Rady Childrens Hosp San Diego, Sch Med, Dept Pediat, Stem Cell Program, La Jolla, CA 92037 - USA

^[3] Tismoo, BR-01401000 Sao Paulo - Brazil

^[4] Univ Sao Paulo, Dept Immunol, Neuroimmune Interact Lab, BR-05508000 Sao Paulo - Brazil

^[5] Univ Sao Paulo, USP Sch Med, Dept Radiol & Oncol, BR-05403010 Sao Paulo - Brazil

^[6] Univ Sao Paulo, Inst Microbiol Sci, Dept Microbiol, Lab Mol Evolut & Bioinformat, BR-05508000 Sao Paulo - Brazil

^[7] Inst Pasteur, Dakar 220 - Senegal

^[8] Univ Sao Paulo, Sch Arts Sci & Humanities, Dept Obstet, BR-03828000 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Nature; v. 534, n. 7606, p. 267+, JUN 9 2016.
• Citações Web of Science: 502

Resumo

Zika virus (ZIKV) is an arbovirus belonging to the genus Flavivirus (family Flaviviridae) and was first described in 1947 in Uganda following blood analyses of sentinel rhesus monkeys(1). Until the twentieth century, the African and Asian lineages of the virus did not cause meaningful infections in humans. However, in 2007, vectored by Aedes aegypti mosquitoes, ZIKV caused the first noteworthy epidemic on Yap Island in Micronesia(2). Patients experienced fever, skin rash, arthralgia and conjunctivitis(2). From 2013 to 2015, the Asian lineage of the virus caused further massive outbreaks in New Caledonia and French Polynesia. In 2013, ZIKV reached Brazil, later spreading to other countries in South and Central America3. In Brazil, the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain-Barre syndrome(4,5). Despite clinical evidence, direct experimental evidence showing that the Brazilian ZIKV (ZIKVBR) strain causes birth defects remains absent(6). Here we demonstrate that ZIKVBR infects fetuses, causing intrauterine growth restriction, including signs of microcephaly, in mice. Moreover, the virus infects human cortical progenitor cells in vitro, leading to an increase in cell death. We also report that the infection of human brain organoids results in a reduction of proliferative zones and disrupted cortical layers. These results indicate that ZIKVBR crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, and impairing neurodevelopment. Our data reinforce the growing body of evidence linking the ZIKVBR outbreak to the alarming number of cases of congenital brain malformations. Our model can be used to determine the efficiency of therapeutic approaches to counteracting the harmful impact of ZIKVBR in human neurodevelopment. (AU)

• Processo FAPESP: 14/17766-9 - Abordagem sistêmica no estudo da permissividade do Anticarsia gemmatalis múltiplo nucleopoliedrovírus (AgMNPV)
• Beneficiário: Paolo Marinho de Andrade Zanotto
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/18703-2 - O papel do eixo triptofano - Kinureninas na regulação da resposta imune através de receptores de glutamato tipo NMDA na encefalomielite experimental auto-imune e na lesão por isquemia e reperfusão cerebral
• Beneficiário: Jean Pierre Schatzmann Peron
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores