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

Abstract

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.

Congenital Zika syndrome is associated with maternal protein malnutrition

“…Placental damage caused by ZIKV has been proven to be an important contributor to embryonic and fetal growth restriction (6,(19)(20)(21). Vasculature damage signatures in the placenta of malnourished and infected cases are comparable to what is described in other in vivo models of ZIKV vertical transmission (19,33). Moreover, necrotic areas found in the labyrinth reflect severe pathological processes occurring in this organ.…”

Zika Virus Causes Persistent Infection in Porcine Conceptuses and may Impair Health in Offspring

“…Studies on pregnant conventional and immunocompromised mice and nonhuman primates (NHP) confirmed detrimental ZIKV-induced congenital pathology and provided insights into ZIKV pathogenesis ( Adams Waldorf et al, 2016 ; Cugola et al, 2016 ; Li et al, 2016 ; Miner et al, 2016 ; Nguyen et al, 2017 ; Tang et al, 2016 ; Vermillion et al, 2017 ; Xavier-Neto et al, 2017 ). However, studies of health sequelae of congenital ZIKV infection in mice proved to be challenging ( Zou and Shi, 2017 ).…”

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

“…In mouse models, strains from the African and Asian lineages were able to establish infection (27)(28)(29)(30). Studies with pregnant animals focused on the strains recently isolated from the Americas or French Polynesia, which were able to cause development problems mimicking the microcephaly observed in humans (15,20,21,31,32). Additionally, ZIKV strains isolated from Brazil and injected into nonhuman primates at high dosages were able to cause alterations in the fetal brain (19).…”