Zika Virus Infects, Activates, and Crosses Brain Microvascular Endothelial Cells, without Barrier Disruption

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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 (ZIKV _MR766 and ZIKV _PE243), which induce increased production of type I and type III IFN, inflammatory cytokines and chemokines. Infection with ZIKV _MR766 promoted earlier cellular death, in comparison to ZIKV _PE243, 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.

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Most cited references 31

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Zika Virus and Birth Defects--Reviewing the Evidence for Causality.

Sonja Rasmussen, Denise Jamieson, Margaret A. Honein … (2016)

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Zika virus cell tropism in the developing human brain and inhibition by azithromycin.

Hanna Retallack, Elizabeth Di Lullo, Carolina Arias … (2016)

The rapid spread of Zika virus (ZIKV) and its association with abnormal brain development constitute a global health emergency. Congenital ZIKV infection produces a range of mild to severe pathologies, including microcephaly. To understand the pathophysiology of ZIKV infection, we used models of the developing brain that faithfully recapitulate the tissue architecture in early to midgestation. We identify the brain cell populations that are most susceptible to ZIKV infection in primary human tissue, provide evidence for a mechanism of viral entry, and show that a commonly used antibiotic protects cultured brain cells by reducing viral proliferation. In the brain, ZIKV preferentially infected neural stem cells, astrocytes, oligodendrocyte precursor cells, and microglia, whereas neurons were less susceptible to infection. These findings suggest mechanisms for microcephaly and other pathologic features of infants with congenital ZIKV infection that are not explained by neural stem cell infection alone, such as calcifications in the cortical plate. Furthermore, we find that blocking the glia-enriched putative viral entry receptor AXL reduced ZIKV infection of astrocytes in vitro, and genetic knockdown of AXL in a glial cell line nearly abolished infection. Finally, we evaluate 2,177 compounds, focusing on drugs safe in pregnancy. We show that the macrolide antibiotic azithromycin reduced viral proliferation and virus-induced cytopathic effects in glial cell lines and human astrocytes. Our characterization of infection in the developing human brain clarifies the pathogenesis of congenital ZIKV infection and provides the basis for investigating possible therapeutic strategies to safely alleviate or prevent the most severe consequences of the epidemic.

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Astrocytes induce blood-brain barrier properties in endothelial cells.

R Janzer, M Raff (1987)

The highly impermeable tight junctions between endothelial cells forming the capillaries and venules in the central nervous system (CNS) of higher vertebrates are thought to be responsible for the blood-brain barrier that impedes the passive diffusion of solutes from the blood into the extracellular space of the CNS. The ability of CNS endothelial cells to form a blood-brain barrier is not intrinsic to these cells but instead is induced by the CNS environment: Stewart and Wiley demonstrated that when avascular tissue from 3-day-old quail brain is transplanted into the coelomic cavity of chick embryos, the chick endothelial cells that vascularize the quail brain grafts form a competent blood-brain barrier; on the other hand, when avascular embryonic quail coelomic grafts are transplanted into embryonic chick brain, the chick endothelial cells that invade the mesenchymal tissue grafts form leaky capillaries and venules. It is, however, not known which cells in the CNS are responsible for inducing endothelial cells to form the tight junctions characteristic of the blood-brain barrier. Astrocytes are the most likely candidates since their processes form endfeet that collectively surround CNS microvessels. In this report we provide direct evidence that astrocytes are capable of inducing blood-brain barrier properties in non-neural endothelial cells in vivo.

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Author and article information

Contributors

Michelle P. Papa: URI : http://loop.frontiersin.org/people/460759/overview

Lana M. Meuren: URI : http://loop.frontiersin.org/people/460725/overview

Sharton V. A. Coelho: URI : http://loop.frontiersin.org/people/460768/overview

Carolina G. de Oliveira Lucas: URI : http://loop.frontiersin.org/people/466687/overview

Yasmin M. Mustafá: URI : http://loop.frontiersin.org/people/466852/overview

Flavio Lemos Matassoli: URI : http://loop.frontiersin.org/people/506431/overview

Paola P. Silveira: URI : http://loop.frontiersin.org/people/506818/overview

Paula S. Frost: URI : http://loop.frontiersin.org/people/506809/overview

Paula Pezzuto: URI : http://loop.frontiersin.org/people/464181/overview

Milene R. Ribeiro: URI : http://loop.frontiersin.org/people/473580/overview

Mauricio L. Nogueira: URI : http://loop.frontiersin.org/people/421619/overview

Loraine Campanati: URI : http://loop.frontiersin.org/people/164219/overview

Marcelo T. Bozza: URI : http://loop.frontiersin.org/people/90340/overview

Heitor A. Paula Neto: URI : http://loop.frontiersin.org/people/405304/overview

Pedro M. Pimentel-Coelho: URI : http://loop.frontiersin.org/people/201407/overview

Claudia P. Figueiredo: URI : http://loop.frontiersin.org/people/466780/overview

Luciana B. de Arruda: URI : http://loop.frontiersin.org/people/353601/overview

Journal

Journal ID (nlm-ta): Front Microbiol

Journal ID (iso-abbrev): Front Microbiol

Journal ID (publisher-id): Front. Microbiol.

Title: Frontiers in Microbiology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-302X

Publication date (Electronic): 22 December 2017

Publication date Collection: 2017

Volume: 8

Electronic Location Identifier: 2557

Affiliations

[1] ¹Departamento de Virologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil

[2] ²Departamento de Imunologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil

[3] ³Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil

[4] ⁴Núcleo de Neurociências da Faculdade de Farmácia, Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil

[5] ⁵Laboratório de Pesquisas em Virologia, Faculdade de Medicina de São José do Rio Preto , São José do Rio Preto, Brazil

[6] ⁶Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil

[7] ⁷Laboratório de Alvos Moleculares, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil

[8] ⁸Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil

Author notes

Edited by: Francois Villinger, University of Louisiana at Lafayette, United States

Reviewed by: Eduardo L. V. Silveira, University of São Paulo, Brazil; Karen M. Smith, University of Louisiana at Lafayette, United States

*Correspondence: Luciana B. de Arruda arruda@ 123456micro.ufrj.br

This article was submitted to Virology, a section of the journal Frontiers in Microbiology

†These authors have contributed equally to this work.

Article

DOI: 10.3389/fmicb.2017.02557

PMC ID: 5743735

PubMed ID: 29312238

SO-VID: e7d1bff7-641e-48a2-a9ed-188680808bef

Copyright © Copyright © 2017 Papa, Meuren, Coelho, Lucas, Mustafá, Lemos Matassoli, Silveira, Frost, Pezzuto, Ribeiro, Tanuri, Nogueira, Campanati, Bozza, Paula Neto, Pimentel-Coelho, Figueiredo, Aguiar and Arruda.

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 16 July 2017

Date accepted : 08 December 2017

Page count

Figures: 7, Tables: 1, Equations: 0, References: 63, Pages: 17, Words: 12296

Funding

Funded by: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior 10.13039/501100002322

Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico 10.13039/501100003593

Funded by: Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro 10.13039/501100004586

Funded by: Financiadora de Estudos e Projetos 10.13039/501100004809

Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo 10.13039/501100001807

Zika Virus Infects, Activates, and Crosses Brain Microvascular Endothelial Cells, without Barrier Disruption

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Abstract

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Zika Virus

Most cited references 31

Zika Virus and Birth Defects--Reviewing the Evidence for Causality.

Zika virus cell tropism in the developing human brain and inhibition by azithromycin.

Astrocytes induce blood-brain barrier properties in endothelial cells.

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