Abstract
Zika virus (ZIKV) has been associated to central nervous system (CNS) harm, and virus was detected in the brain and cerebrospinal fluids of microcephaly and meningoencephalitis cases. However, the mechanism by which the virus reaches the CNS is unclear. Here, we addressed the effects of ZIKV replication in human brain microvascular endothelial cells (HBMECs), as an in vitro model of blood brain barrier (BBB), and evaluated virus extravasation and BBB integrity in an in vivo mouse experimental model. HBMECs were productively infected by African and Brazilian ZIKV strains (ZIKVMR766 and ZIKVPE243), which induce increased production of type I and type III IFN, inflammatory cytokines and chemokines. Infection with ZIKVMR766 promoted earlier cellular death, in comparison to ZIKVPE243, but infection with either strain did not result in enhanced endothelial permeability. Despite the maintenance of endothelial integrity, infectious virus particles crossed the monolayer by endocytosis/exocytosis-dependent replication pathway or by transcytosis. Remarkably, both viruses' strains infected IFNAR deficient mice, with high viral load being detected in the brains, without BBB disruption, which was only detected at later time points after infection. These data suggest that ZIKV infects and activates endothelial cells, and might reach the CNS through basolateral release, transcytosis or transinfection processes. These findings further improve the current knowledge regarding ZIKV dissemination pathways.
Highlights
Zika virus (ZIKV) is an arthropod-borne virus, from Flaviviridae family, genus Flavivirus, which is associated with a large spectrum of clinical manifestations and different forms of transmission, being a unique Arbovirus (WHO, 2016)
We demonstrated that ZIKV infection of brain endothelial cells result in cellular activation and release of infectious virus particles, with no increase of endothelial monolayer permeability in vitro and no significant disruption of blood brain barrier (BBB) in vivo
That article described that human brain microvascular endothelial cells (HBMECs) became resistant to IFN effects and to virus-induced cell death, and that ZIKV infection did not result in increased permeability of HBMECs (Mladinich et al, 2017)
Summary
Zika virus (ZIKV) is an arthropod-borne virus (arbovirus), from Flaviviridae family, genus Flavivirus, which is associated with a large spectrum of clinical manifestations and different forms of transmission, being a unique Arbovirus (WHO, 2016). ZIKV circulation positively correlated with enormous increase in the number of cases of microcephaly, suggesting a causal association between ZIKV infection during pregnancy and neonatal microcephaly (Calvet et al, 2016; Oliveira Melo et al, 2016; Rasmussen et al, 2016; Schuler-Faccini et al, 2016) This was further supported by virus detection in the brains and in amniotic fluid of fetuses with microcephaly by qRT-PCR, immunohistochemistry and electron microscopy (Calvet et al, 2016; Martines et al, 2016; Mlakar et al, 2016). Meningoencephalitis was reported in ZIKV-infected adult patients and during experimental infection of rhesus monkeys, and the viral RNA was detected in their cerebrospinal fluid (Carteaux et al, 2016; Dudley et al, 2016) These lines of evidence suggest that virus replication may be, eventually, associated to invasion of central nervous system (CNS)
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