Experimental Zika Virus Infection in the Pregnant Common Marmoset Induces Spontaneous Fetal Loss and Neurodevelopmental Abnormalities

Abstract

During its most recent outbreak across the Americas, Zika virus (ZIKV) was surprisingly shown to cause fetal loss and congenital malformations in acutely and chronically infected pregnant women. However, understanding the underlying pathogenesis of ZIKV congenital disease has been hampered by a lack of relevant in vivo experimental models. Here we present a candidate New World monkey model of ZIKV infection in pregnant marmosets that faithfully recapitulates human disease. ZIKV inoculation at the human-equivalent of early gestation caused an asymptomatic seroconversion, induction of type I/II interferon-associated genes and proinflammatory cytokines, and persistent viremia and viruria. Spontaneous pregnancy loss was observed 16-18 days post-infection, with extensive active placental viral replication and fetal neurocellular disorganization similar to that seen in humans. These findings underscore the key role of the placenta as a conduit for fetal infection, and demonstrate the utility of marmosets as a highly relevant model for studying congenital ZIKV disease and pregnancy loss.

Mathematical modeling of within‐host Zika virus dynamics

“…Zika virus infection of pregnant macaques (Figure A) results in prolonged maternal viremia as well as fetal pathology and ZIKV infection of the fetus, mimicking features of human infection. Similar results have also been found in marmosets . These studies in primate models thus provide valuable data to aid understanding of the factors affecting fetal viral burden and the associated risk of severe fetal outcomes.…”

Timing of gestational exposure to Zika virus is associated with postnatal growth restriction in a murine model

“…In contrast, in other nonhuman primate models, including our common marmoset model, infection of the placenta did not lead to significant inflammation although significant infection and even fetal loss still occurred. 27 The lack of placental inflammation other than macrophage hyperplasia has also been described in human beings as well. 28 Therefore, although it is established that the placenta acts as a reservoir and conduit for fetal infection, the implication of placental dysfunction with ZIKV infection in the development of CZS in human beings is less clear.…”

Vector-borne transmission and evolution of Zika virus

“…Subsequent sequencing of amplified products indicated that they were identical to ZIKV strains circulating epidemically at the time, suggesting that they could serve as reservoirs for enzootic transmission. In addition, recent experimental ZIKV infections of marmosets reproduced key features of human ZIKV infection and viremia titers were near the necessary threshold for transmission 55,56 .…”