Abstract
A small percentage of babies born to Zika virus (ZIKV)-infected mothers manifest severe defects at birth, including microcephaly. Among those who appeared healthy at birth, there are increasing reports of postnatal growth or developmental defects. However, the impact of congenital ZIKV infection in postnatal development is poorly understood. Here, we report that a mild congenital ZIKV-infection in pups born to immunocompetent pregnant mice did not display apparent defects at birth, but manifested postnatal growth impediments and neurobehavioral deficits, which include reduced locomotor and cognitive deficits that persisted into adulthood. We found that the brains of these pups were smaller, had a thinner cortical layer 1, displayed increased astrogliosis, decreased expression of microcephaly- and neuron development- related genes, and increased pathology as compared to mock-infected controls. In summary, our results showed that even a mild congenital ZIKV infection in immunocompetent mice could lead to postnatal deficits, providing definitive experimental evidence for a necessity to closely monitor postnatal growth and development of presumably healthy human infants, whose mothers were exposed to ZIKV infection during pregnancy.
Highlights
Despite being discovered about 70 years ago, Zika virus (ZIKV) had not gained much public health attention until its massive outbreak in Brazil in 2015, whereby it has been suggested as a causative agent of microcephaly and other congenital birth defects in human newborns whose mothers were exposed to ZIKV during their first trimester of pregnancy (Campos et al, 2015)
Postnatal behavioral abnormalities were observed in (C57BL/6) mice that were inoculated directly within the amniotic fluid of the uterus, resulting in ocular deficits that contributed to behavioral deficits, viral RNA was detected in fetal brains at birth and at day 8 post-birth (Cui et al, 2017), indicating viral infection lasted into postnatal development in this model
Our results showed that newborn pups from ZIKV infected immunocompetent dams were free of ZIKV RNA and had similar head size and body weight with mock-infected control pups, yet manifested postnatal growth impediments and neurobehavioral deficits that persisted into adulthood
Summary
Despite being discovered about 70 years ago, ZIKV had not gained much public health attention until its massive outbreak in Brazil in 2015, whereby it has been suggested as a causative agent of microcephaly and other congenital birth defects in human newborns whose mothers were exposed to ZIKV during their first trimester of pregnancy (Campos et al, 2015). To study the postnatal developmental impacts of congenital ZIKV infection in mouse pups (denoted ZIKV-pups), we inoculated pregnant immunocompetent C57BL/6J mice intraperitoneally (i.p.) at embryonic day (E) 8.5 with PBS (mock) or 104 PFU of ZIKV strain PRVABC59, which is closely related to the epidemic strains that have been linked to human microcephaly in the Americas (Faria et al, 2016).
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