Zika virus exposure affects neuron-glia communication in the hippocampal slices of adult rats

Abstract

Zika virus (ZIKV) infection during pregnancy was associated with microcephaly in neonates, but clinical and experimental evidence indicate that ZIKV also causes neurological complications in adults. However, the changes in neuron-glial communication, which is essential for brain homeostasis, are still unknown. Here, we report that hippocampal slices from adult rats exposed acutely to ZIKV showed significant cellular alterations regarding to redox homeostasis, inflammatory process, neurotrophic functions and molecular signalling pathways associated with neurons and glial cells. Our findings support the hypothesis that ZIKV is highly neurotropic and its infection readily induces an inflammatory response, characterized by an increased expression and/or release of pro-inflammatory cytokines. We also observed changes in neural parameters, such as adenosine receptor A2a expression, as well as in the release of brain-derived neurotrophic factor and neuron-specific enolase, indicating plasticity synaptic impairment/neuronal damage. In addition, ZIKV induced a glial commitment, with alterations in specific and functional parameters such as aquaporin 4 expression, S100B secretion and glutathione synthesis. ZIKV also induced p21 senescence-associated gene expression, indicating that ZIKV may induce early senescence. Taken together, our results indicate that ZIKV-induced neuroinflammation, involving nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor κB (NFκB) pathways, affects important aspects of neuron-glia communication. Therefore, although ZIKV infection is transient, long-term consequences might be associated with neurological and/or neurodegenerative diseases.

Gliotoxicity and Glioprotection: the Dual Role of Glial Cells

“…In both astrocytes and microglia, ZIKV elicited classical inflammatory responses [ 96 ], while, for astrocytes, it induced oxidative stress, mitochondrial failure, and DNA damage in astrocytes [ 97 ]. Our group have demonstrated that an acute hippocampus exposure to ZIKV is also able to induce neuroinflammation and oxidative stress, affecting neuron-glia communication [ 98 ].…”

Neurodevelopment in Children Exposed to Zika in utero: Clinical and Molecular Aspects

“…The association of ZIKV to other neurological manifestations have also been described and suggested, beyond that observed in congenital Zika syndrome ( Lebov et al, 2018 ; Beys-da-Silva et al, 2019 ; 2020 ; Bobermin et al, 2020 ). Molecularly, according to the review of DEGs in ZIKV infection, other brain diseases can be potentially linked to virus exposure ( Figure 6B ).…”

“…ZIKV can also affect the immunological and oxidative responses associated with astrocytes ( Ledur et al, 2020 ). Moreover, ZIKV was able to replicate in an experimental model of adult brain tissue ( Figueiredo et al, 2019 ), as well as affected neuron-glia communication in the hippocampus ( Bobermin et al, 2020 ), suggesting that neurological consequences in Zika-infected adults need more studies and clinical observations. By understanding the interaction among neurons and glial cells, preventive/therapeutic strategies may emerge.…”

Acute neurologic emerging flaviviruses

“… 122 In vitro studies of human and mouse brain tissue suggest that ZIKV can replicate within human and mouse brain cells and may lead to memory and synaptic changes via virus-induced inflammation and disrupted neuronal–glial communication. 123 , 124 This suggests that patients with a history of Zika infection may be at a higher risk of neurodegeneration and need to be monitored for clinical signs.…”