Peripheral blood mononuclear cells increase the permeability of dengue virus-infected endothelial cells in association with downregulation of vascular endothelial cadherin

Dewi, Beti Ernawati; Takasaki, Tomohiko; Kurane, Ichiro

doi:10.1099/vir.0.83356-0

Cited by 54 publications

(57 citation statements)

References 52 publications

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“…3A and C to E). Previous studies aiming to understand the role of DENV infection in increased vascular permeability have also reported important changes in either epithelial or endothelial barrier permeability after interaction with CM from DENV-infected cells (51,52).…”

Section: Figmentioning

confidence: 99%

The Cytokine Response of U937-Derived Macrophages Infected through Antibody-Dependent Enhancement of Dengue Virus Disrupts Cell Apical-Junction Complexes and Increases Vascular Permeability

Puerta-Guardo¹,

Raya‐Sandino²,

González‐Mariscal³

et al. 2013

J Virol

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Severe dengue (SD) is a life-threatening complication of dengue that includes vascular permeability syndrome (VPS) and respiratory distress. Secondary infections are considered a risk factor for developing SD, presumably through a mechanism called antibody-dependent enhancement (ADE). Despite extensive studies, the molecular bases of how ADE contributes to SD and VPS are largely unknown. This work compares the cytokine responses of differentiated U937 human monocytic cells infected directly with dengue virus (DENV) or in the presence of enhancing concentrations of a humanized monoclonal antibody recognizing protein E (ADE-DENV infection). Using a cytometric bead assay, ADE-DENV-infected cells were found to produce significantly higher levels of the proinflammatory cytokines interleukin 6 (IL-6), IL-12p70, and tumor necrosis factor alpha (TNF-␣), as well as prostaglandin E 2 (PGE 2 ), than cells directly infected. The capacity of conditioned supernatants (conditioned medium [CM]) to disrupt tight junctions (TJs) in MDCK cell cultures was evaluated. Exposure of MDCK cell monolayers to CM collected from ADE-DENV-infected cells (ADE-CM) but not from cells infected directly led to a rapid loss of transepithelial electrical resistance (TER) and to delocalization and degradation of apical-junction complex proteins. Depletion of either TNF-␣, IL-6, or IL-12p70 from CM from ADE-DENV-infected cells fully reverted the disrupting effect on TJs. Remarkably, mice injected intraperitoneally with ADE-CM showed increased vascular permeability in sera and lungs, as indicated by an Evans blue quantification assay. These results indicate that the cytokine response of U937-derived macrophages to ADE-DENV infection shows an increased capacity to disturb TJs, while results obtained with the mouse model suggest that such a response may be related to the vascular plasma leakage characteristic of SD.

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Section: Figmentioning

confidence: 99%

The Cytokine Response of U937-Derived Macrophages Infected through Antibody-Dependent Enhancement of Dengue Virus Disrupts Cell Apical-Junction Complexes and Increases Vascular Permeability

Puerta-Guardo¹,

Raya‐Sandino²,

González‐Mariscal³

et al. 2013

J Virol

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“…Therefore, despite the activation of adhesion molecules ICAM-1 and VCAM-1 on endothelial cells, permeability was unchanged following exposure to TNF-containing supernatants from dengue virus-infected mast cells. Previous reports of TNF-induced permeability of HUVECs required very high concentrations of TNF (10 to 1,000 ng/ml), in some instances, in combination with ongoing dengue virus infection (13,14,30). However, the physiological relevance of such effects is uncertain since the average TNF levels detected in DHF patient sera are 20 to 40 pg/ml (3,11,24,40).…”

mentioning

confidence: 97%

“…CCL2 has also been reported to increase permeability in endothelial monolayers through disruption of tight junctions (28). Additionally, coculture of peripheral blood mononuclear cells promotes changes in dengue virusinfected HUVECs, including decreased vascular endothelial cadherin expression and increased permeability (14). Finally, TNF has been shown to enhance dengue-induced NO and reactive oxygen species effects on endothelial cell damage and hemorrhage in a mouse model of dengue virus infection (50).…”

mentioning

confidence: 99%

Dengue Virus Infection of Mast Cells Triggers Endothelial Cell Activation

Brown

Hermann

Issekutz

et al. 2011

J Virol

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Vascular perturbation is a hallmark of severe forms of dengue disease. We show here that antibodyenhanced dengue virus infection of primary human cord blood-derived mast cells (CBMCs) and the human mast cell-like line HMC-1 results in the release of factor(s) which activate human endothelial cells, as evidenced by increased expression of the adhesion molecules ICAM-1 and VCAM-1. Endothelial cell activation was prevented by pretreatment of mast cell-derived supernatants with a tumor necrosis factor (TNF)-specific blocking antibody, thus identifying TNF as the endothelial cell-activating factor. Our findings suggest that mast cells may represent an important source of TNF, promoting vascular endothelial perturbation following antibody-enhanced dengue virus infection.Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) represent the most life-threatening clinical outcomes of dengue virus infections. The immunopathological mechanisms are significant and include antibody-dependent enhancement of dengue virus infection, a known risk factor in the development of DHF/DSS (18). A major distinguishing feature of DHF/DSS is plasma leakage; therefore, much attention has been directed to mechanisms of vascular endothelial dysfunction. Histological damage to the vascular endothelium in DHF cases is usually limited to swelling and occasional intercellular gaps (41), suggesting that endothelial perturbation is mediated by subtle immunopathological effects rather than by cytopathological virus infection. Dengue virus infection promotes upregulation of membrane-associated and soluble adhesion molecules which are indicative of endothelial cell activation (1, 36). These parameters correlate with disease severity (9,21,25,34,43).Mast cells are connective tissue-associated leukocytes located at areas of external interface, such as the skin and mucous membranes. They are in close proximity to blood vessels, with functional roles in a variety of inflammatory conditions (i.e., asthma and allergy) and innate protection against pathogens. The evidence for mast cell involvement in dengue disease includes observations that dengue patients exhibit increased levels of blood and urinary histamine (a product of mast cells and basophils), which correlates with disease severity (37,47). A large histological study of DHF patients noted that mast cells in the connective tissue around the thymus showed swelling, vacuolation of the cytoplasm, and loss of granule integrity, suggestive of mast cell activation (5). Mast cells are also involved in skin eruptions (rash), a common feature of dengue virus infection (19,35,42,48).We have previously reported that human mast cells are permissive to antibody-enhanced dengue virus infection, occurring in an Fc␥RII-dependent manner (6, 23). Infection of mast cell lines KU812 and HMC-1 results in infectious virus production and the induction of significant levels of cytokines, such as interleukin-1␤ (IL-1␤) and IL-6, as well as chemokines CCL3, CCL4, and CCL5, which can recruit additional immune effector...

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“…27 We considered that this low susceptibility of EC to DENV-2 infection noted above could be due to 1 donor variation, heterogeneity in the primary HUVEC population or variation in EC susceptibility due 2 to the location in the body they are isolated from. To address this we next DENV-infected primary quantified SK1 activity in DENV-infected EC lysates.…”

mentioning

confidence: 99%

Dengue Virus Infection of Primary Endothelial Cells Induces Innate Immune Responses, Changes in Endothelial Cells Function and Is Restricted by Interferon-Stimulated Responses

Calvert

Helbig

Dimasi

et al. 2015

Journal of Interferon & Cytokine Research

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1 Although endothelial cell (EC) infection is not widespread during dengue virus (DENV) infection in 2vivo, the endothelium is the site of the pathogenic effects seen in severe DENV disease. In this study 3 we investigated DENV infection of primary EC and defined factors that influence infection in this cell 4 type. 5Consistent with in vivo findings where EC infection is infrequent, only 3-15% of EC became 6 productively DENV-2-infected in vitro. This low level infection could not be attributed to inhibition 7 by heparin, EC donor variation, heterogeneity, or biological source. DENV-infection of EC was 8 associated with induction of innate immune responses, including increased STAT1 protein, STAT1-9 phosphorylation, and IFN-β, OAS-1, IFIT-1/ISG56 and viperin mRNA. Antibody blocking of IFN-β 10 inhibited the induction of OAS1, IFIT1/ISG56 and viperin while shRNA knockdown of viperin 11 enhanced DENV-infection in EC. DENV-infection of EC resulted in increased activity of 12 sphingosine kinase 1, a factor important in maintaining vascular integrity, and altered basal and 13 stimulated changes in barrier integrity of DENV-infected EC monolayers. 14 Thus, DENV productively infects only a small percentage of primary EC but this has a major 15 influence on induction of IFN-β driven innate immune responses that can restrict infection while the 16 EC themselves are functionally altered. These changes may have important consequences for the 17 endothelium and are reflective of pathogenic changes associated with vascular leakage, as seen in 18 DENV disease.

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Peripheral blood mononuclear cells increase the permeability of dengue virus-infected endothelial cells in association with downregulation of vascular endothelial cadherin

Cited by 54 publications

References 52 publications

The Cytokine Response of U937-Derived Macrophages Infected through Antibody-Dependent Enhancement of Dengue Virus Disrupts Cell Apical-Junction Complexes and Increases Vascular Permeability

The Cytokine Response of U937-Derived Macrophages Infected through Antibody-Dependent Enhancement of Dengue Virus Disrupts Cell Apical-Junction Complexes and Increases Vascular Permeability

Dengue Virus Infection of Mast Cells Triggers Endothelial Cell Activation

Dengue Virus Infection of Primary Endothelial Cells Induces Innate Immune Responses, Changes in Endothelial Cells Function and Is Restricted by Interferon-Stimulated Responses

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