Congenital Zika Virus Infection in Immunocompetent Mice Causes Postnatal Growth Impediment and Neurobehavioral Deficits

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.

Neurodevelopment of children exposed intra-uterus by Zika virus: A case series

“…In our cohort, the most affected component was language. These results agree with several studies that used animal models and suggested ZIKV infection could cause postnatal developmental deficit [25,26].…”

“…This is one of the hypothesis to explain cerebral injury [32]. Additionally lesions indicative of deep gray matter injury, vascular compromise and neuroprogenitor cell dysfunction are describe [25,26,33].…”

Congenital Zika syndrome is associated with maternal protein malnutrition

“…In our assays, we found body weight reduction in infected malnourished litters, consistent with the findings in human CZS cases. A recent study on wild-type C57BL/6J mice have found that vertical transmission of ZIKV after intraperitoneal injection on pregnant females does not result in morphological alterations in the offspring during perinatal life but negative outcomes appeared later in postnatal life (31). This coincides with our results of Co/ZIKV in which we confirmed ZIKV congenital infection, but we did not find phenotypic signals of CZS in embryos and neonates.…”

Subclinical in utero Zika virus infection is associated with interferon alpha sequelae and sex-specific molecular brain pathology in asymptomatic porcine offspring

“…In a pigtail macaque model, maternal ZIKV inoculation during gestation resulted in substantial brain lesions and silent brain pathology (i.e., periventricular T2-hyperintense foci and loss of fetal noncortical brain volume, injury to the ependymal epithelium with underlying gliosis, and loss of late fetal neuronal progenitor cells) in fetuses, even in the absence of microcephaly [10,11]. Two very recent studies in immunocompetent mouse models reported neurocognitive disorders and neurobehavioral deficits in offspring affected with mild congenital ZIKV infection [12,13]. These pioneering studies provided critical information regarding outcomes of mild congenital ZIKV infection in mouse offspring.…”