Asian Pacific Journal of Tropical Medicine
Intracellular calcium ions facilitate dengue virus entry into endothelial cells and compromise endothelial barrier integrity

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This study received funding from the Ministry of Higher Education Malaysia via the Higher Institution Centre of Excellence (HICoE) program (MO002-2019) and Development of Research Institute for Excellent Enterprises (ATC+) Project, Republic of Korea (IF001-2021).

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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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Shu MH, Wong PF, Sam SS, Loong SK, Teoh BT, AbuBakar S. Intracellular calcium ions facilitate dengue virus entry into endothelial cells and compromise endothelial barrier integrity. Asian Pac J Trop Med 2021; 14(11): 505- 516.

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  • Received:September 02,2021
  • Revised:November 22,2021
  • Adopted:November 23,2021
  • Online: November 30,2021
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