Ocular and uteroplacental pathology in macaque congenital Zika virus infection

Abstract

Congenital Zika virus (ZIKV) infection impacts fetal development and pregnancy outcomes. We infected a pregnant rhesus macaque with a Puerto Rican ZIKV isolate in the first trimester. The pregnancy was complicated by preterm premature rupture of membranes (PPROM) and fetal demise 49 days post infection (gestational day 95). Significant pathology at the maternal-fetal interface included acute chorioamnionitis, placental infarcts, and leukocytoclastic vasculitis of the myometrial radial arteries. ZIKV RNA was disseminated throughout the fetus tissues and maternal immune system at necropsy, as assessed by quantitative RT-PCR for viral RNA. Replicating ZIKV was identified in fetal tissues, maternal lymph node, and maternal spleen by fluorescent in situ hybridization for viral replication intermediates. Fetal ocular pathology included a choroidal coloboma, suspected anterior segment dysgenesis, and a dysplastic retina. This is the first report of ocular pathology and prolonged viral replication in both maternal and fetal tissues following congenital ZIKV infection in rhesus macaques. PPROM followed by fetal demise and severe pathology of the visual system have not been described in macaque congenital infection previously; further nonhuman primate studies are needed to determine if an increased risk for PPROM is associated with congenital Zika virus infection.\n\nAuthor summaryA ZIKV infection during pregnancy is associated with malformations in fetal development including, but not limited to, ocular and brain anomalies, such as microcephaly, and stillbirth. The development of an accurate pregnancy model to study the effects of ZIKV will provide insight into vertical transmission, ZIKV tissue distribution, and fetal injury and malformations. Non-human primates closely resemble human in terms of the reproductive system, immunity, placentation and pregnancy. Our study demonstrates that the rhesus macaque is a compelling model in which to study ZIKV during pregnancy due to similar outcomes between the human and rhesus macaque. These similarities include prolonged viremia, vertical transmission, adverse pregnancy outcomes and fetal pathology, including defects in the visual system.