Zika virus infection in immunocompetent pregnant mice causes fetal damage and placental pathology in the absence of fetal infection

Abstract

Zika virus (ZIKV) infection during human pregnancy may cause diverse and serious congenital defects in the developing fetus. Previous efforts to generate animal models of human ZIKV infection and clinical symptoms often involved manipulating mice to impair their Type I interferon (IFN) signaling, thereby allowing enhanced infection and vertical transmission of virus to the embryo. Here, we show that even pregnant mice competent to generate Type I IFN responses that can limit ZIKV infection nonetheless develop profound placental pathology and high frequency of fetal demise. We consistently found that maternal ZIKV exposure led to placental pathology and that ZIKV RNA levels measured in maternal, placental or embryonic tissues were not predictive of the pathological effects seen in the embryos. Placental pathology included trophoblast hyperplasia in the labyrinth, trophoblast giant cell necrosis in the junctional zone, and loss of embryonic vessels. Our findings suggest that, in this context of limited infection, placental pathology rather than embryonic/fetal viral infection may be a stronger contributor to adverse pregnancy outcomes in mice. Our finding demonstrates that in immunocompetent mice, direct viral infection of the embryo is not essential for fetal demise. Our immunologically unmanipulated pregnancy mouse model provides a consistent and easily measurable congenital abnormality readout to assess fetal outcome, and may serve as an additional model to test prophylactic and therapeutic interventions to protect the fetus during pregnancy, and for studying the mechanisms of ZIKV congenital immunopathogenesis.

The effect of Zika virus infection in the ferret

“…Ferrets often have large litters, strengthening their attractiveness as an animal model to study viral infections. It is not clear why select animals in a litter become more strongly infected than others and show different characteristics, but similar outcomes have been reported for human pregnancies in that only a fraction of women with Zika virus infections give birth to infants with microcephaly; in addition, maternal infection levels and fetal outcome may not be strongly related (Brasil, et al, ) (Szaba et al, ). A recent report by the CDC, however, suggests that babies born to infected mothers show symptoms consistent with learning disabilities as they develop over the first year or two of life.…”

“…This may also partially explain why we did not see a viral titer in the blood of the mother, if the placenta is an important site of Zika replication. Szaba et al ()) reported that even low levels of maternal infection can cause substantial placental infection and variable effects in the fetus. In addition, each placenta may not have the same access to the virus through its individual umbilical vein.…”

“…This may also partially explain why we did not see a viral titer in the blood of the mother, if the placenta is an important site of Zika replication. Szaba et al (2018) Infection of the placenta is therefore an important factor that might impact the cerebral vasculature and lead to poorly formed blood vessels. We did not specifically evaluate the vasculature of the placenta in this study.…”

IL-1 receptor antagonist therapy mitigates placental dysfunction and perinatal injury following Zika virus infection

“…Similarly, placental vascular development was dysregulated by in utero ZIKV infection, as evidenced by a significant decrease in endothelial cell density. This disruption to the normal placental architecture may have affected the anchoring of the placenta into the uterine wall and the nutrient exchange between the dam and fetuses, which are necessary for fetal development (67,68).…”

Summit proceedings: Biomedical countermeasure development for emerging vector-borne viral diseases

“…The Model relevance was also discussed in the context of a Zika pregnancy model in immunocompetent mice, in which the infected dams did not get viremia and there was no detectable vertical transmission of virus, yet there was virtually 100% fetal demise. Monoclonal antibody blocking studies indicated that, despite the absence of productive infection, the pathology was apparently caused by virus, raising the possibility of fetal demise due to specific placental pathology [7]. There would be great value in developing high quality, standardized animal models and challenge strains of particular pathogens that are broadly accepted.…”