Evolution of ocular defects in infant macaques following in utero Zika virus infection
Glenn Yiu, Sara M. Thomasy, M. Isabel Casanova, Alexander Rusakevich, Rebekah I. Keesler, Jennifer Watanabe, Jodie Usachenko, Anil Singapuri, Erin E. Ball, Eliza Bliss-Moreau, Wendi Guo, Helen Webster, Tulika Singh, Sallie Permar, Amir Ardeshir, Lark L. Coffey, Koen K.A. Van Rompay
Glenn Yiu, Sara M. Thomasy, M. Isabel Casanova, Alexander Rusakevich, Rebekah I. Keesler, Jennifer Watanabe, Jodie Usachenko, Anil Singapuri, Erin E. Ball, Eliza Bliss-Moreau, Wendi Guo, Helen Webster, Tulika Singh, Sallie Permar, Amir Ardeshir, Lark L. Coffey, Koen K.A. Van Rompay
View: Text | PDF
Research Article Immunology Ophthalmology

Evolution of ocular defects in infant macaques following in utero Zika virus infection

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.

Authors

Glenn Yiu, Sara M. Thomasy, M. Isabel Casanova, Alexander Rusakevich, Rebekah I. Keesler, Jennifer Watanabe, Jodie Usachenko, Anil Singapuri, Erin E. Ball, Eliza Bliss-Moreau, Wendi Guo, Helen Webster, Tulika Singh, Sallie Permar, Amir Ardeshir, Lark L. Coffey, Koen K.A. Van Rompay

×

Figure 1

History of infant macaques exposed in utero to ZIKV infection.

Options: View larger image (or click on image) Download as PowerPoint
History of infant macaques exposed in utero to ZIKV infection. (A) Schem...
(A) Schematic of experimental design. Pregnant macaques were inoculated by both i.v. and intra-amniotic routes between GDs 42 and 53 followed by frequent monitoring. Whereas 4 dams had fetal loss or stillbirth, the other 2 animals delivered infants that were dam-reared, subsequently weaned and then housed together until they were euthanized at approximately 2 years of age. The patterns of viral RNA levels in plasma (B) and amniotic fluid (C) of the pregnant dams that delivered live infants were similar to those for animals whose fetuses died and reflects prolonged virus replication. The dotted lines show the limit of detection. (D) The 2 ZIKV-exposed infants had normal weight gain. Green dots indicate historical control data (15,585 data points collected from n = 284 female animals over the first 2 years of life). (E) Anti-ZIKV antibodies in plasma of dams and infants measured by whole-virion ELISA, showing rapid loss of ZIKV IgG in congenitally exposed infants after birth and gradual decline of IgG in ZIKV-infected dams. Magnitude of ZIKV-specific IgG is expressed as the log of ED50. ZIKV, Zika virus; GDs, gestational days; ED50, 50% of maximal effective dilution.