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.
Highlights
Zika virus (ZIKV) is a mosquito-borne flavivirus that was initially thought to produce a benign disease characterized by mild fever, muscle and joint pain, rash and conjunctivitis [1]
As the 4G2 antibody detects a flaviviral E protein epitope, we further confirmed the identity of ZIKV by sequencing an amplicon of the ZIKV E-protein gene, which established it as a bona fide fragment of the ZIKV genome
Notwithstanding the close similarity of our frequencies with the reported low prevalence of congenital defects associated with ZIKV in the human setting the defects we report are admittedly relatively infrequent
Summary
Zika virus (ZIKV) is a mosquito-borne flavivirus that was initially thought to produce a benign disease characterized by mild fever, muscle and joint pain, rash and conjunctivitis [1]. It is becoming increasingly clear that ZIKV pathogenicity is not restricted to the aforementioned conditions [7]. In order to face the challenges posed by an infectious agent with such potential, the scientific community worldwide directed its attention to the biology of ZIKV and its pathogenicity. At this junction, there are few clues on the mechanisms triggered by viral infection to damage the embryonic and/or fetal human.
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