Serum from dengue virus-infected patients with and without plasma leakage differentially affects endothelial cells barrier function in vitro

Abstract

BackgroundAlthough most of cases of dengue infections are asymptomatic or mild symptomatic some individuals present warning signs progressing to severe dengue in which plasma leakage is a hallmark.Methodology/Principal findingsThe present study used Electric Cell-substrate Impedance Sensing (ECIS®) which allows for electrical monitoring of cellular barrier function measuring changes in Transendothelial Electric Resistance (TEER) to investigate the parameters associated with dengue induced leakage. Three groups of individuals were tested: dengue-positives with plasma leakage (leakage), dengue-positives without plasma leakage (no leakage), and dengue-negatives (control). Data show that TEER values of human umbilical vein endothelial cells (HUVECs) was significantly lower after incubation with serum from subjects of the leakage group in comparison to the no leakage or control groups. The serum levels of CXCL1, EGF, eotaxin, IFN-γ, sCD40L, and platelets were significantly decreased in the leakage group, while IL-10, IL-6, and IP-10 levels were significantly increased. We also found a strong correlation between TEER values and augmented levels of IP-10, GM-CSF, IL-1α, and IL-8, as well as decreased levels of CXCL1 and platelets.Conclusions/SignificanceThe present work shows that the magnitude of the immune response contributes to the adverse plasma leakage outcomes in patients and that serum components are important mediators of changes in endothelial homeostasis during dengue infections. In particular, the increased levels of IP-10 and the decreased levels of CXCL1 and platelets seem to play a significant role in the disruption of vascular endothelium associated with leakage outcomes after DENV infection. These findings may have important implications for both diagnostic and therapeutic approaches to predict and mitigate vascular permeabilization in those experiencing the most severe clinical disease outcomes after dengue infection.

Plectin is Required for Trans‐Endothelial Permeability: A Model of Plectin Dysfunction in Human Endothelial Cells After TNF‐α Treatment and Dengue Virus Infection

“…Several mediators, including histamine, TNF‐α, and vascular endothelial growth factor, have been suggested as playing a role in inducing tyrosine phosphorylation of VE‐cadherin, β‐catenin, and p‐120, thus increasing endothelial barrier permeability . The results of in vitro study of the effect of EC barrier function caused by treatment with serum from dengue patients with plasma leakage have been described . Those results also suggest that the high level of IP‐10, and low level of CXCL1 and platelets may play a role in the disruption of vascular endothelium resulting in vascular leakage after DENV infection.…”

Dengue Virus Induces the Release of sCD40L and Changes in Levels of Membranal CD42b and CD40L Molecules in Human Platelets

“…A significant role of sCD40L in both inflammation and the humoral immune response is therefore likely [ 5 ]. Giving further support to an important biological role of sCD40L in dengue is the decreased serum concentration of this molecule recently identified in patients with the virus [ 35 ].…”

Rift valley fever viral load correlates with the human inflammatory response and coagulation pathway abnormalities in humans with hemorrhagic manifestations

“…Of these only eotaxin was correlated with viral load. Eotaxin is a pro-inflammatory cytokine that mediates chemotaxis of eosinophils, basophils, mast cells, and Th2 lymphocytes during infection and has been noted to be lower in some patients with dengue infection when compared to controls, particularly patients with significant vascular leakage [ 30 ]. Further research using larger numbers of patients should be conducted to understand if RVF disease severity or clinical manifestations correlate with expression of these cytokines.…”