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ORIGINAL ARTICLE
Year : 2021  |  Volume : 14  |  Issue : 11  |  Page : 505-516

Intracellular calcium ions facilitate dengue virus entry into endothelial cells and compromise endothelial barrier integrity


1 Tropical Infectious Diseases Research and Education Centre (TIDREC), Universiti Malaya, 50603 Kuala Lumpur, Malaysia
2 Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
3 Tropical Infectious Diseases Research and Education Centre (TIDREC); World Health Organization Collaborating Centre for Arbovirus Reference and Research (Dengue and Severe Dengue) MAA-12, Universiti Malaya, 50603 Kuala Lumpur, Malaysia

Correspondence Address:
Pooi-Fong Wong
Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur
Malaysia
Sazaly AbuBakar
Tropical Infectious Diseases Research and Education Centre (TIDREC); World Health Organization Collaborating Centre for Arbovirus Reference and Research (Dengue and Severe Dengue) MAA-12, Universiti Malaya, 50603 Kuala Lumpur
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1995-7645.331257

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Objective: To investigate the involvement of Ca2+ in dengue virus (DENV)-infected human umbilical vein endothelial cells (HUVECs) and the disruption of endothelial integrity. Methods: HUVECs were infected with DENV-2 in the presence of intracellular Ca2+ or endoplasmic reticulum Ca2+ chelators. Virus infectivity was measured by focus-forming assay and quantitative RT-PCR. Intracellular Ca2+ was measured using Fluo-4-AM dye. VE-cadherin and focal adhesion kinase (FAK) expressions were investigated by immunofluorescence and immunoblotting assays, respectively. Results: DENV infection increased intracellular cytosolic Ca2+ levels and caused disassembly of the adherens junction protein, VE- cadherin as evidenced by decreased VE-cadherin expression at the periphery of DENV-2 infected HUVECs. Depletion of intracellular Ca2+ stores, particularly those of the endoplasmic reticulum Ca2+, significantly decreased DENV yield in HUVECs. Decreased virus yield following the depletion of intracellular Ca2+ was caused by the inhibition of viral entry into HUVECs and not the inhibition of viral binding or attachment. DENV-2 infection also resulted in Ca2+-dependent activation of FAK. Conclusions: Intracellular Ca2+ is required for the early phases of DENV infection in endothelial cells. Increased cytosolic Ca2+ levels in endothelial cells during DENV infection activated FAK, disrupted adherens junctions and compromised barrier integrity. Thus, Ca2+ plays an important role in DENV infection in endothelial cells.


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