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Zika Virus NS1 Suppresses VE-Cadherin and Claudin-5 via hsa-miR-101-3p in Human Brain Microvascular Endothelial Cells

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Abstract

Zika virus (ZIKV) is a neurotropic virus that causes microcephaly in newborns and Guillain-Barré syndrome (GBS) in adults. ZIKV is known to transmigrate through the blood–brain barrier (BBB) by utilizing different strategies. NS1 is a conserved flavivirus protein, which is secreted extracellularly. ZIKV-NS1 has been shown to target adherens junctions (AJs) and tight junctions (TJs) to disrupt the endothelial barrier integrity. The microRNAs are short non-coding RNAs, which post-transcriptionally regulate the gene expression by binding to 3’ UTR of the target gene. In the present study, we studied the ZIKV-NS1-mediated effect through hsa-miR-101-3p on the junctional barrier integrity in human brain microvascular endothelial cells. We exposed hBMVECs and hCMEC/D3 cells with ZIKV-NS1 at different time points (12 h and 24 h) with the doses 500 ng/mL and 1000 ng/mL. The change in the expression of VE-cadherin and claudin-5 was quantified using immunoblotting. The expression of the hsa-miR-101-3p was quantified using qRT-PCR. To prove the targeting of hsa-miR-101-3p to VE-cadherin, we transfected hsa-miR-101-3p mimic, scramble, hsa-miR-101-3p inhibitor, and Cy3 in the ZIKV-NS1-exposed hCMEC/D3 cells. The distribution and expression of the VE-cadherin and claudin-5 were observed using immunofluorescence and immunoblotting. The ZIKV-NS1 compromises the endothelial barrier integrity by disrupting the VE-cadherin and claudin-5 protein expression via hsa-miR-101-3p. The findings of this study suggest that ZIKV-NS1 dysregulates the adherens junction and tight junction proteins through hsa-miR-101-3p, which compromises the barrier integrity of human brain microvascular endothelial cells.

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Data Availability

All data generated in this study are available from the corresponding author on reasonable request.

Abbreviations

ZIKV:

Zika virus

RNA:

Ribonucleic acid

miRNA:

MicroRNA

NS1:

Non-structural protein 1

hBMVECSs:

Primary human brain microvascular endothelial cells

hCMEC/D3:

Human brain microvascular endothelial cell line

BBB:

Blood–brain barrier

VE-cadherin:

Vascular endothelial cadherin

FBS:

Fetal bovine serum

JEV:

Japanese encephalitis virus

WNV:

West Nile virus

DENV:

Dengue virus

YFV:

Yellow fever virus

TBEV:

Tick-borne encephalitis virus

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Acknowledgements

The authors are highly thankful to Dr. Meghana Rastogi and Ms. Neha Pandey for providing their crucial help during the experiments and manuscript drafting. The authors acknowledge the support provided through the Institute of Eminence Scheme (IoE-6031) of Banaras Hindu University, Varanasi, India.

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  1. Molecular Biology Unit, Faculty of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India

    Utkarsh Bhardwaj & Sunit K. Singh

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  1. Utkarsh Bhardwaj
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  2. Sunit K. Singh
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UB designed and conducted experiments, performed data analysis, and wrote the initial draft of the manuscript. SKS conceived the idea, supervised the experiments, and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Sunit K. Singh.

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Bhardwaj, U., Singh, S.K. Zika Virus NS1 Suppresses VE-Cadherin and Claudin-5 via hsa-miR-101-3p in Human Brain Microvascular Endothelial Cells. Mol Neurobiol 58, 6290–6303 (2021). https://doi.org/10.1007/s12035-021-02548-x

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