Cytokine Factors Present in Dengue Patient Sera Induces Alterations of Junctional Proteins in Human Endothelial Cells

Appanna, Ramapraba; Wang, Seok Mui; Ponnampalavanar, Sasheela A P Sri La Sri; Lum, Lucy Chai See; Sekaran, Shamala Devi

doi:10.4269/ajtmh.2012.11-0606

Cited by 45 publications

(48 citation statements)

References 19 publications

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“…This evidence indicates that the epithelial barrier dysfunction observed as a reduction in TER is a consequence of circulating soluble factors present in the ADE-CM. Interestingly, a recent report suggests that cytokine factors present in serum samples collected from patients with SD induced morphological alterations in human umbilical vein endothelial cells (HUVECs) with perturbations in the ZO-1 and VE-cadherin proteins (63). Thus, a risk connection between the proinflammatory immune response of ADE-DENV-infected macrophages and the phenomenon of barrier dysfunction observed in patients with VPS can now be proposed.…”

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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“…There is increasing evidence that the immune system plays a key role in determining the severity of dengue disease [18,19], in particular the array of cytokines produced during infection [8,9,10,24]. The role of T lymphocytes in this process is controversial since on the one hand there is evidence that activation of T lymphocytes leads to pro-inflammatory cytokine synthesis [20,21,22,23,24,25,26,27] and on the other there is evidence that T-lymphocyte proliferation in dengue patients is impaired [28,29,30,31] and that patients with acute DENV infection are leukopenic [28,29].…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms that lead to these clinical outcomes are unknown, however there is growing evidence that the pathophysiology of dengue is mediated by host immune response [2,4]. Several lines of evidence indicate that anti-dengue antibodies [5,6,7], cytokines [8,9,10], soluble immune mediators [11,12,13] and cross-reactive memory T lymphocytes [14,15,16], along with high dengue viral loads [17], contribute to the progression to DHF/DSS and death [18,19]. …”

Section: Introductionmentioning

confidence: 99%

Dengue Virus Serotype-2 Impairs Proliferation of Healthy Donors' T Lymphocytes

et al. 2014

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Objectives: T lymphocytes are not infected by dengue virus (DENV), nevertheless it is possible that exposure to DENV may affect their function. T lymphocytes from DENV-infected individuals are impaired in their proliferative capacity, although this effect has been attributed to altered function of antigen-presenting cells rather than to an intrinsic defect on T lymphocytes. Here we analyzed whether T lymphocytes from healthy donors became impaired in their proliferative capacity following in vitro exposure to DENV serotype-2 (DENV-2), as well as the possible mechanisms for this. Methods: Isolated CD4+ and CD8+ T lymphocytes from healthy donors were in vitro exposed to DENV-2, before polyclonal activation, cell proliferation, IL-2 synthesis. IL-2Rα expression, nuclear translocation of NF-AT and NF-κB, and intracellular calcium flux were assessed. Results: In vitro exposure of both CD4+ and CD8+ T lymphocytes from healthy donors to DENV-2 impairs cell proliferation, IL-2 synthesis, and IL-2Rα (CD25) cell membrane expression. Signalling wise, exposure to DENV-2 impairs the nuclear translocation of NF-AT, downstream of intracellular calcium mobilization, as well as that of NF-κB. Conclusion: In the course of a dengue infection, direct exposure of T lymphocytes to DENV could affect cell-mediated immune responses.

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“…14,17 The factors that cause vascular leak are thought to be present in serum of dengue patients, as sera from dengue patients have shown to reduce expression of gap junction proteins thus leading to vascular leak. 18 Among the potential mediators that cause vascular leak, VEGF has been extensively studied in dengue, 19,20 and it has been shown that free plasma VEGF levels are significantly higher and VEGF receptor 2 levels are significantly lower in those with DHF. 20 In addition, the rise in VEGF and fall in VEGFR2 was shown to correlate with the onset of vascular leak.…”

Section: Mediators That Cause Vascular Leakmentioning

confidence: 99%

Mediators of vascular leak in dengue infections

Malavige

2016

J of Cey Coll of Phy

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Although plasma leakage is the hallmark of severe dengue infections the factors that cause increased vascular permeability have not been identified. As platelet activating factor (PAF), lipid mediators and cytokines are associated with increase in vascular permeability, we set out to investigate the role of these mediators in acute dengue infection.Levels of inflammatory lipid mediators and cytokines were initially evaluated in 25 patients with confirmed acute dengue infection and 12 healthy individuals. After determining which inflammatory mediators were associated with severe dengue, serial assays of the above lipid mediators, and cytokines were done in an additional 36 patients in serum samples collected 12 hours apart throughout the course of their hospital stay.We found that PAF levels were significantly higher in patients (p=0.001) when compared to healthy individuals and that PAF levels rose just before the onset of the critical phase. PAF values of >100ng/ml were associated with reduced expression of gap junction proteins leading to increased vascular permeability. A similar effect was seen with serum from patients with dengue infection which was reversed by a PAF receptor antagonist. S1P levels which are associated with increasing the integrity of the endothelial barrier were significantly reduced in patients with DHF. Serum IL-10, TNFand IL-1 levels were elevated in patients with DHF and followed the same patterns as PAF. In conclusion, our results show that PAF is likely to be a potent mediator of vascular leak in dengue and use of PAF blockers could be therapeutically useful. and is one of the major emerging infectious diseases. It has been predicted that 390 million dengue infections occur per year resulting in approximately 96 million clinically apparent infections.

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Cytokine Factors Present in Dengue Patient Sera Induces Alterations of Junctional Proteins in Human Endothelial Cells

Cited by 45 publications

References 19 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 Serotype-2 Impairs Proliferation of Healthy Donors' T Lymphocytes

Mediators of vascular leak in dengue infections

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