Selective Disruption of the Blood-Brain Barrier by Zika Virus.

Ana Rachel Leda,Nazira El-Hage,Michal Toborek,Madhavan Nair,Luc Bertrand,Ibolya Edit Andras

doi:10.3389/fmicb.2019.02158

Ana Rachel Leda, Nazira El-Hage + Show 4 more

Open Access

https://doi.org/10.3389/fmicb.2019.02158

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Abstract

The blood–brain barrier (BBB) selectively regulates the cellular exchange of macromolecules between the circulation and the central nervous system (CNS). Here, we hypothesize that Zika virus (ZIKV) infects the brain via a disrupted BBB and altered expression of tight junction (TJ) proteins, which are structural components of the BBB. To assess this hypothesis, in vitro and in vivo studies were performed using three different strains of ZIKV: Honduras (ZIKV-H), Puerto Rico (ZIKV-PR), and Uganda (ZIKV-U). Primary human brain microvascular endothelial cells (BMECs) were productively infected by all studied ZIKV strains at MOI 0.01, and were analyzed by plaque assay, immunofluorescence for NS1 protein, and qRT-PCR at 2 and 6 days post-infection (dpi). Compared to mock-infected controls, expression level of ZO-1 was significantly upregulated in ZIKV-H-infected BMECs, while occludin and claudin-5 levels were significantly downregulated in BMECs infected by all three studied viral strains. Interestingly, BMEC permeability was not disturbed by ZIKV infection, even in the presence of a very high viral load (MOI 10). All studied ZIKV strains productively infected wild-type C57BL/J mice after intravenous infection with 107 PFU. Viral load was detected in the plasma, spleen, and brain from 1 to 8 dpi. Peak brain infection was observed at 2 dpi; therefore, TJ protein expression was assessed at this time point. Claudin-5 was significantly downregulated in ZIKV-U-infected animals and the BBB integrity was significantly disturbed in ZIKV-H-infected animals. Our results suggest that ZIKV penetrates the brain parenchyma early after infection with concurrent alterations of TJ protein expression and disruption of the BBB permeability in a strain-dependent manner.

Highlights

Neurotropic viral infection can directly and indirectly disrupt the complex structural and functional architecture of the central nervous system (CNS)
blood–brain barrier (BBB) dysfunction appears to be the main route for viral neuroinvasion, and it is preceded by changes in the expression of cytokines, chemokines, cell adhesion molecules (Kim, 2008), and disruption of tight junction (TJ) integrity, as observed in human immunodeficiency virus (HIV) (Pu et al, 2005; Toborek et al, 2005; Strazza et al, 2011; McRae, 2016; Bertrand et al, 2019a), hepatitis C virus (HCV) (Liu et al, 2009; Crema et al, 2015), and West Nile virus (WNV) (Neal, 2014; Suen et al, 2014) infections
Our first approach was to verify the infectivity of different strains of Zika virus (ZIKV) in brain microvascular endothelial cells (BMECs), the main component of the BBB

Summary

Introduction

Neurotropic viral infection can directly and indirectly (e.g., by inducing local immune responses) disrupt the complex structural and functional architecture of the central nervous system (CNS). BBB dysfunction appears to be the main route for viral neuroinvasion, and it is preceded by changes in the expression of cytokines, chemokines, cell adhesion molecules (Kim, 2008), and disruption of tight junction (TJ) integrity, as observed in human immunodeficiency virus (HIV) (Pu et al, 2005; Toborek et al, 2005; Strazza et al, 2011; McRae, 2016; Bertrand et al, 2019a), hepatitis C virus (HCV) (Liu et al, 2009; Crema et al, 2015), and West Nile virus (WNV) (Neal, 2014; Suen et al, 2014) infections. These viruses have significant neuroinvasive characteristics and are regarded as neurotropic (Neal, 2014)

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