The Neurobiology of Zika Virus: New Models, New Challenges

Abstract

The Zika virus (ZIKV) attracted attention due to one striking characteristic: the ability to cross the placental barrier and infect the fetus, possibly causing severe neurodevelopmental disruptions included in the Congenital Zika Syndrome (CZS). Few years after the epidemic, the CZS incidence has begun to decline. However, how ZIKV causes a diversity of outcomes is far from being understood. This is probably driven by a chain of complex events that relies on the interaction between ZIKV and environmental and physiological variables. In this review, we address open questions that might lead to an ill-defined diagnosis of CZS. This inaccuracy underestimates a large spectrum of apparent normocephalic cases that remain underdiagnosed, comprising several subtle brain abnormalities frequently masked by a normal head circumference. Therefore, new models using neuroimaging and artificial intelligence are needed to improve our understanding of the neurobiology of ZIKV and its true impact in neurodevelopment.

Zika virus induced microcephaly and aberrant hematopoietic cell differentiation modeled in novel neonatal humanized mice

“…The plethora of congenital pathologic lesions usually precipitate devastating neuropathology including microcephaly, cognitive development due to cerebral hypoplasia, and blindness ( 81 – 83 ). In our study, we were able to mimic microcephaly syndrome with a smaller head circumference, overall brain hypoplasia and consequent neuronal syndromes similar to that seen in humans ( 9 ). Our model is unique in that we were able to document the neurological effects of ZIKV postnatally to determine how the virus elicits CZS.…”

“…Additionally, infants with congenital Zika infection have presented with a high rate of ocular abnormalities due to retinal lesions, chorioretinal atrophy, and optic nerve abnormalities ( 6 , 7 ). The constellation of symptoms due to ZIKV infection that include microcephaly, neuromotor deficits, epileptic seizures, tremors, calcifications, and arthrogryposis are now collectively known as congenital Zika syndrome (CZS) ( 8 , 9 ). Many of these children that have developed CZS from in utero exposure will suffer lifelong long-term effects of severe intellectual disability resulting in significant financial burdens ( 10 ).…”

Zika Virus: A New Therapeutic Candidate for Glioblastoma Treatment

“…Further evidence that ZIKV abrogates neurogenesis was provided by Garcez et al [24], who reported a reduced viability and growth of human iPSC-derived NSCs cultured as neurospheres and organoids. An additional study also hypothesized that ZIKV induces a programmed neural cell death, thus causing the disruption of crucial events of early embryonic neurodevelopment [78]. Programmed cell death is essential during morphogenesis, since it helps sculpt brain development.…”

“…An interesting observation from in vitro studies is that several cells could be the target of ZIKV. While studies in human iPSC-derived neural cells have highlighted the widespread infection and apoptosis of NPCs [78], other studies have indicated that more mature cells, including neurons, radial glial cells, and astrocytes can also be the target [81,82]. Interestingly, radial glia and astrocytes were reported to be more susceptible to infection than neurons [16], because ZIKV replicates more efficiently in undifferentiated compared to differentiated cells [83].…”