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

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...

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Published in:	PLoS neglected tropical diseases Vol. 11; no. 2; p. e0005363
Main Authors:	Xavier-Neto, Jose, Carvalho, Murilo, Pascoalino, Bruno Dos Santos, Cardoso, Alisson Campos, Costa, Ângela Maria Sousa, Pereira, Ana Helena Macedo, Santos, Luana Nunes, Saito, Ângela, Marques, Rafael Elias, Smetana, Juliana Helena Costa, Consonni, Silvio Roberto, Bandeira, Carla, Costa, Vivian Vasconcelos, Bajgelman, Marcio Chaim, de Oliveira, Paulo Sérgio Lopes, Cordeiro, Marli Tenorio, Gonzales Gil, Laura Helena Vega, Pauletti, Bianca Alves, Granato, Daniela Campos, Paes Leme, Adriana Franco, Freitas-Junior, Lucio, Holanda de Freitas, Carolina Borsoi Moraes, Teixeira, Mauro Martins, Bevilacqua, Estela, Franchini, Kleber
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 23-02-2017 Public Library of Science (PLoS)
Subjects:	Animal models Animals Arthrogryposis - embryology Arthrogryposis - immunology Arthrogryposis - pathology Arthrogryposis - virology Biology and Life Sciences Colleges & universities Complications and side effects Development and progression Developmental biology Disease Models, Animal Edema Embryos Female Fetuses Genetic disorders Humans Hydrocephalus - embryology Hydrocephalus - immunology Hydrocephalus - pathology Hydrocephalus - virology Laboratories Male Medicine and Health Sciences Mice Mice, Inbred C57BL Microcephaly Morphology Placenta - abnormalities Placenta - immunology Placenta - virology Pregnancy Pregnancy Complications, Infectious - immunology Pregnancy Complications, Infectious - pathology Pregnancy Complications, Infectious - virology Research and Analysis Methods Teratogenesis Teratogens - analysis Tropical diseases Vector-borne diseases Zika virus Zika Virus - physiology Zika virus infection Zika Virus Infection - embryology Zika Virus Infection - immunology Zika Virus Infection - pathology Zika Virus Infection - virology
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Summary:	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 well as arthrogryposis, a set of abnormal joint postures observed in the human setting. Late exposure to ZIKV at 12.5 dpc failed to produce noticeable malformations. We have thus characterized a developmental window of opportunity for ZIKV-induced teratogenesis encompassing early gastrulation, neurulation and early organogenesis stages. This should not, however, be interpreted as evidence for any safe developmental windows for ZIKV exposure. Late developmental abnormalities correlated with damage to the placenta, particularly to the labyrinthine layer, suggesting that circulatory changes are integral to the altered phenotypes.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors have declared that no competing interests exist. Conceptualization: JXN MC BdSP ACC AMSC AHMP LNS JHCS MCB PSLdO AFPL LFJ CBMHdF MMT EB KF.Data curation: JXN MC ACC LNS AS REM.Formal analysis: JXN MC BdSP ACC AMSC AHMP LNS AS REM JHCS SRC CB VVC MCB PSLdO MTC LHVGG BAP DCG AFPL LFJ CBMHdF MMT EB KF.Funding acquisition: JXN.Investigation: JXN MC BdSP ACC AMSC AHMP LNS AS JHCS SRC CB VVC MCB MTC LHVGG BAP DCG AFPL LFJ CBMHdF MMT EB.Methodology: JXN MC BdSP ACC AMSC AHMP LNS AS REM JHCS SRC CB VVC MCB PSLdO MTC LHVGG BAP DCG AFPL LFJ CBMHdF MMT EB.Project administration: JXN MC KF.Resources: KF.Software: PSLdO.Supervision: JXN KF.Visualization: MC.Writing – original draft: JXN MC BdSP ACC AMSC AHMP LNS AS REM JHCS SRC CB VVC MCB PSLdO MTC LHVGG BAP DCG AFPL LFJ CBMHdF MMT EB KF.Writing – review & editing: JXN KF.
ISSN:	1935-2735 1935-2727 1935-2735
DOI:	10.1371/journal.pntd.0005363