Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain

Abstract

Zika virus (ZIKV) is a flavivirus with teratogenic effects on the fetal brain, but the spectrum of brain injury is unknown, particularly when ultrasound imaging is normal. In a pregnant pigtail macaque (Macaca nemestrina) model, we demonstrate that ZIKV injury to the fetal brain was significant even in the absence of microcephaly and is clinically challenging to detect. A common and subtle injury pattern was identified including: 1) periventricular T2-hyperintense foci and loss of fetal non-cortical brain volume, 2) injury to the ependymal epithelium with underlying gliosis, and 3) loss of late fetal neuronal progenitor cells in the subventricular zone (temporal cortex) and subgranular zone (dentate gyrus, hippocampus) with dysmorphic granule neuron patterning. Attenuation of fetal neurogenic output demonstrates potentially significant teratogenic effects of congenital ZIKV infection even without microcephaly. All children exposed to ZIKV in utero should be followed long-term for neurocognitive deficits, regardless of head size at birth.

Postnatal Zika virus infection is associated with persistent abnormalities in brain structure, function, and behavior in infant macaques

“…Similar to the fetal brain injury observed after maternal ZIKV infection in a pigtail macaque model as well as congenital ZIKV syndrome in humans (2, 26, 62, 63), our analysis of postnatal ZIKV infection in RM infants revealed inflammation, reactive astrocytes, gliosis in the grey and white matter, axonal injury, and apoptosis in the brain and spinal cord. In particular, the consistent finding of astrogliosis between the infant infection model described here and fetal infection illustrates a common pathology of postnatal and in utero ZIKV infection (63). In our model, ZIKV RNA was not detected in the brain regions showing increased apoptosis and gliosis, suggesting these abnormalities may be due to an indirect inflammatory mechanism rather than direct cytopathic effect of the virus.…”

Zika Virus as a Possible Risk Factor for Autism Spectrum Disorder: Neuroimmunological Aspects

“…At the present moment, it is too early to assess cognitive abilities in these children [6, 23, 24]. Adams et al [25], in a study in macaques, have demonstrated that even in the absence of microcephaly, the teratogenic action of ZIKV infection in the fetal brain is substantial and has long-lasting effects. These effects on the fetal brain include loss of fetal noncortical brain volume, injury to the ependymal epithelium, and loss of late fetal neuronal progenitor cells.…”

A previously undetected pathology of Zika virus infection

“…Three of the monkeys also received a monoclonal dengue virus antibody to model the effects of pre-exposure to another flavivirus. However, as Adams Waldorf et al 7 acknowledge, the small number of monkeys and multiple treatment conditions in this experimental design preclude any definitive conclusion about whether dengue antibodies potentiate the deleterious effects of ZIKV infections. Following inoculation with ZIKV, none of the fetuses developed microcephaly, and weekly ultrasounds did not reveal any gross fetal abnormalities until gestational day 100.…”

“…Congenital Zika syndrome has now been defined as a spectrum of abnormalities that range far beyond microcephaly to include other severe impairments, such as craniofacial disproportion, ocular anomalies, and intracranial calcifications, but the nature and extent of potential Zika-related pathology is still not fully understood. Here, Adams Waldorf et al 7 further study offspring of ZIKV-infected pigtail macaques and identify indications of neurological damage in the absence of microcephaly.…”

“…In this study, Adams Waldorf et al 7 inoculated five pregnant pigtail macaques with either the Cambodian or Brazilian strain of ZIKV to track the emergence of pathology in neurogenic regions in utero and to identify any notable effects on the brain at full-term delivery. Monkeys were infected at different time points during pregnancy, ranging from day 60 to day 119 of the typical 170-d gestational period (Fig.…”