Abstract

Zika virus (ZIKV) infection during pregnancy causes a wide spectrum of congenital abnormalities and postnatal developmental sequelae such as fetal loss, intrauterine growth restriction (IUGR), microcephaly, or motor and neurodevelopmental disorders. Here, we investigated whether a mouse pregnancy model recapitulated a wide range of symptoms after congenital ZIKV infection, and whether the embryonic age of congenital infection changed the fetal or postnatal outcomes. Infection with ZIKV strain PRVABC59 from embryonic day 6.5 (E6.5) to E8.5, corresponding to the mid-first trimester in humans, caused fetal death, fetal resorption, or severe IUGR, whereas infection from E9.5 to E14.5, corresponding to the late-first to second trimester in humans, caused stillbirth, neonatal death, microcephaly, and postnatal growth deficiency. Furthermore, 4-week-old offspring born to dams infected at E12.5 showed abnormalities in neuropsychiatric state, motor behavior, autonomic function, or reflex and sensory function. Thus, our model recapitulated the multiple symptoms seen in human cases, and the embryonic age of congenital infection was one of the determinant factors of offspring outcomes in mice. Furthermore, maternal neutralizing antibodies protected the offspring from neonatal death after congenital infection at E9.5, suggesting that neonatal death in our model could serve as criteria for screening of vaccine candidates.

Highlights

  • The World Health Organization declared the outbreak of Zika virus (ZIKV) infection in the American continent as a public health emergency of international concern in 2016

  • To assess fetal outcomes after congenital ZIKV infection, dams were s.c. infected with PRVABC59 at E6.5, E7.5, E8.5, E9.5, E10.5, E11.5, E12.5, E13.5, and E14.5, and the fetuses were visually inspected at 6 days post-infection

  • Dams were infected with ZIKV at the indicated embryonic days

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Summary

Introduction

The World Health Organization declared the outbreak of Zika virus (ZIKV) infection in the American continent as a public health emergency of international concern in 2016. ZIKV causes a spectrum of congenital abnormalities including fetal loss, intrauterine growth restriction (IUGR), neonatal death, and microcephaly, together termed congenital Zika syndrome (CZS), which is likely associated with complex and life-long disabilities in children born to women infected with ZIKV during pregnancy [1,2,3,4,5,6] Postnatal developmental sequelae, such as gross motor impairment, delayed neurodevelopment, cognitive impairment, auditory abnormalities, and/or ophthalmological abnormalities have been recognized after congenital ZIKV infection, [7,8,9,10,11,12,13,14,15,16]. IFNα/β receptor knockout (IFNAR−/− ) dams that were crossed with wild-type sires were infected subcutaneously (s.c.) with ZIKV at various embryonic days, and a series of fetal and postnatal outcomes were comprehensively evaluated

Ethics Statement
Cell and Virus Stocks
Virus Titration
Statistical Analyses
Fetal Outcomes
Fetal and Placental Infection
Postnatal Outcomes
Maternal Neutralizing Antibodies Prevent Offspring Outcomes
Conclusions
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