Hydrocephalus and arthrogryposis in an immunocompetent mouse model of ZIKA teratogeny: A developmental study

作者：José Xavier‐Neto, Murilo de Carvalho, Bruno dos Santos Pascoalino, Alisson C. Cardoso, Ângela Maria Sousa Costa, Ana Helena Macedo Pereira, Luana Nunes Santos, Ângela Saito, Rafael Elias Marques, Juliana Helena Costa Smetana, Sílvio Roberto Consonni, Carla Letícia Bandeira, Vivian Vasconcelos Costa, Marcio C. Bajgelman, Paulo Sérgio Lopes de Oliveira, Marli Tenório Cordeiro, Laura H. V. G. Gil, Bianca Alves Pauletti, Daniela C. Granato, Adriana Franco Paes Leme, Lúcio H. Freitas-Júnior, Carolina Borsoi Moraes, Mauro Martins Teixeira, Estela Bevilacqua, Kleber G. Franchini · 发表于：PLoS neglected tropical diseases · 年份：2017 · DOI：10.1371/journal.pntd.0005363 · 被引用次数：111 · 研究领域：Parvovirus B19 Infection Studies、Prenatal Screening and Diagnostics、Virology and Viral Diseases

The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infection. The model utilizes immunocompetent animals from wild-type FVB/NJ and C57BL/6J strains, providing a better analogy to the human condition than approaches involving immunodeficient, genetically modified animals, or direct ZIKV injection into the brain. When injected via the jugular vein into the blood of pregnant females harboring conceptuses from early gastrulation to organogenesis stages, akin to the human second and fifth week of pregnancy, ZIKV infects maternal tissues, placentas and embryos/fetuses. Early exposure to ZIKV at developmental day 5 (second week in humans) produced complex manifestations of anterior and posterior dysraphia and hydrocephalus, as well as severe malformations and delayed development in 10.5 days post-coitum (dpc) embryos. Exposure to the virus at 7.5-9.5 dpc induces intra-amniotic hemorrhage, widespread edema, and vascular rarefaction, often prominent in the cephalic region. At these stages, most affected embryos/fetuses displayed gross malformations and/or intrauterine growth restriction (IUGR), rather than isolated microcephaly. Disrupted conceptuses failed to achieve normal developmental landmarks and died in utero. Importantly, this is the only model so far to display dysraphia and hydrocephalus, the harbinger of microcephaly in humans, as wel...