A neonatal nonhuman primate model of gestational Zika virus infection with evidence of microencephaly, seizures and cardiomyopathy.

Rosemary J Steinbach,Takeshi F Andoh,Alec J Hirsch,Jonah B Sacha,Anne D Lewis,Christopher D Kroenke,Xiaojie Wang,Robert M Friedman,Antonio E Frias,Travis Hodge,Heidi L Pecoraro,Jonathan R Lindner,Meredith A Kelleher,Terry K Morgan,Marjorie R Grafe,Robert L Schelonka,Peter Stenzel,Trevor J Mcgill,Brandy L Dozier,Edward Porsov,J Beth Kempton,Victoria H J Roberts,Lisa A Houser,Craig N Kreklywich,Christopher J Parkins,Martha Neuringer,Jessica L Smith,John V Brigande,Justin M Greene,Lauren Renner ,Nicole Haese ,Lois M.a Colgin ,Rhonda Macallister ,Daniel N Streblow

doi:10.1371/journal.pone.0227676

Abstract

Zika virus infection during pregnancy is associated with miscarriage and with a broad spectrum of fetal and neonatal developmental abnormalities collectively known as congenital Zika syndrome (CZS). Symptomology of CZS includes malformations of the brain and skull, neurodevelopmental delay, seizures, joint contractures, hearing loss and visual impairment. Previous studies of Zika virus in pregnant rhesus macaques (Macaca mulatta) have described injury to the developing fetus and pregnancy loss, but neonatal outcomes following fetal Zika virus exposure have yet to be characterized in nonhuman primates. Herein we describe the presentation of rhesus macaque neonates with a spectrum of clinical outcomes, including one infant with CZS-like symptoms including cardiomyopathy, motor delay and seizure activity following maternal infection with Zika virus during the first trimester of pregnancy. Further characterization of this neonatal nonhuman primate model of gestational Zika virus infection will provide opportunities to evaluate the efficacy of pre- and postnatal therapeutics for gestational Zika virus infection and CZS.

Highlights

Zika virus (ZIKV) is a mosquito-borne and sexually transmissible flavivirus endemic to central Africa and Southeast Asia, that has recently emerged in the Western Hemisphere
ZIKV RNA was detected in the peripheral blood plasma of all infected dams, with peak viremia occurring between 1–4 days post infection (DPI) (Fig 2)
In this study of gestational Zika virus infection in rhesus macaques we have identified a range of pregnancy complications, placental injury, and postnatal neurological and cardiac abnormalities

Summary

Introduction

Zika virus (ZIKV) is a mosquito-borne and sexually transmissible flavivirus endemic to central Africa and Southeast Asia, that has recently emerged in the Western Hemisphere. ZIKV infection in pregnant women increases the risk of miscarriage, preterm birth and congenital defects in affected infants. Neurological disorders, musculoskeletal abnormalities, auditory and visual impairment— symptomology collectively referred to congenital Zika syndrome (CZS) [3,4,5]. Thousands of infants with CZS have been born to ZIKV exposed mothers since the beginning of the Western Hemisphere outbreak. Estimates of penetrance of adverse outcomes of congenital ZIKV infection have varied widely by region. In a cohort of 182 women with confirmed ZIKV infection in Rio de Janeiro, Brazil, adverse outcomes were observed in 46% of pregnancies [3]. Functional assessment of vision in infants born with laboratory confirmation of ZIKV infection showed abnormalities in 92.6% of cases [14]. Sensorineural hearing loss, sleep disorders, and feeding complications including difficulty swallowing have been recorded in children up to 2 years of age [9, 11, 15]

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Conclusion