Abstract
Congenital Zika syndrome (CZS) is associated with microcephaly and various neurological, musculoskeletal, and ocular abnormalities, but the long-term pathogenesis and postnatal progression of ocular defects in infants are not well characterized. Rhesus macaques are superior to rodents as models of CZS because they are natural hosts of the virus and share similar immune and ocular characteristics, including blood–retinal barrier characteristics and the unique presence of a macula. Using a previously described model of CZS, we infected pregnant rhesus macaques with Zika virus (ZIKV) during the late first trimester and characterized postnatal ocular development and evolution of ocular defects in 2 infant macaques over 2 years. We found that one of them exhibited colobomatous chorioretinal atrophic lesions with macular and vascular dragging as well as retinal thinning caused by loss of retinal ganglion neuron and photoreceptor layers. Despite these congenital ocular malformations, axial elongation and retinal development in these infants progressed at normal rates compared with healthy animals. The ZIKV-exposed infants displayed a rapid loss of ZIKV-specific antibodies, suggesting the absence of viral replication after birth, and did not show any behavioral or neurological defects postnatally. Our findings suggest that ZIKV infection during early pregnancy can impact fetal retinal development and cause congenital ocular anomalies but does not appear to affect postnatal ocular growth.
Highlights
Zika virus (ZIKV) is a mosquito-transmitted flavivirus that was first isolated from a rhesus macaque in the Zika Forest of Uganda in 1947
The 2 infants described in this manuscript were part of a study in which 6 pregnant macaques were each inoculated once, between gestational day (GD) 42 and 53 with 2000 PFUs of 2 ZIKV strains isolated from 2015 outbreaks, by both the i.v. and IA routes (Figure 1A)
The 2 other pregnant dams had no clinical symptoms and each gave birth to a female infant by natural delivery on GDs 168 and 171, respectively. Both these dams had patterns of high-peak plasma viremia at 5 or 6 log10 vRNA copies per mL and prolonged detection of viral RNA in amniotic fluid samples that decreased toward the end of pregnancy in a pattern similar to the 4 dams that lost their fetus or infants (Figure 1, B and C) and to historical data of animals inoculated by these same routes [31]
Summary
Zika virus (ZIKV) is a mosquito-transmitted flavivirus that was first isolated from a rhesus macaque in the Zika Forest of Uganda in 1947. The spectrum of fetal and neonatal anomalies, including microcephaly, ocular defects, musculoskeletal contractures, and neurologic deficits, combined with a diagnosis of prenatal ZIKV infection, together constitute congenital Zika syndrome (CZS). The predilection for CNS abnormalities in CZS is explained by the tropism of ZIKV for neural progenitor cells [2]. Studies indicate this may be due to the binding of the viral RNA genome to the RNA-binding protein Musashi-1 that is involved in neurodevelopment and is highly expressed in these precursor neurons [3]. Because many infants whose mothers are ZIKV-infected during pregnancy are born without microcephaly or detectable viral RNA in fluids, but may develop neurologic problems later in life, long-term monitoring of these young children is essential [5,6,7]
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