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.

Evidence of natural Zika virus infection in neotropical non-human primates in Brazil

“…The molecular investigation of ZIKV in different NHP organs suggested a widespread viral distribution. We detected the highest ZIKV loads, indirectly measured by the Cts, in the kidneys, brain and spleen, which is in accordance with previous observations in rhesus monkeys and common marmosets experimentally infected with ZIKV 13 , 16 , 33 , 34 . Not all organs showed the presence of ZIKV RNA (Table 1 ).…”

“…While adult males did not present and signs of clinical disease, viremia was detected resulting in their seroconversion and protection from subsequent ZIKV infection 13 . Likewise, the pregnant marmoset dams exhibited prolonged viremia, viruria and seroconversion, as previously observed in humans 14 , 15 , as well as viral replication in the placenta 16 .…”

“…Callithrix and Sapajus species have distinct geographic distributions along the different Brazilian biomes and importantly this species’ distribution range extends well within several urban settings 22 , 23 . Additionally, it was recently demonstrated that three other neotropical NHP species can support ZIKV infection and thus can serve as reservoir and amplification hosts into a sylvatic transmission cycle 11 , 13 , 16 .…”

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.…”

“…Similar results have also been found in marmosets. 50 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.…”