Productive Dengue Virus Infection of Human Endothelial Cells Is Directed by Heparan Sulfate-Containing Proteoglycan Receptors

Dalrymple, Nadine A.; Mackow, Erich R.

doi:10.1128/jvi.05008-11

Cited by 108 publications

(105 citation statements)

References 81 publications

(108 reference statements)

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“…21 In addition to the effect of inflammatory cytokines, other mechanisms may also be involved, including direct interaction of dengue virus with endothelial cells, release of mast cell products, and pro-coagulant factors such as thrombin. [21][22][23][24][25] No definite conclusion on a causal relationship of Ang-1 and Ang-2 levels and plasma leakage could be made in this observational study. Similar trends in Ang-1 and Ang-2 levels have been found in severe malaria and sepsis, 26,27 but in contrast to DHF/DSS and sepsis, plasma leakage is not a prominent feature of malaria.…”

Section: Discussionmentioning

confidence: 90%

Imbalance of Angiopoietin-1 and Angiopoetin-2 in Severe Dengue and Relationship with Thrombocytopenia, Endothelial Activation, and Vascular Stability

Michels¹,

Ven²,

Djamiatun³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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Abstract. The pathogenesis of plasma leakage during dengue hemorrhagic fever/dengue shock syndrome (DHF/ DSS) is largely unknown. Angiopoietins are key regulators of vascular integrity: Angiopoietin-1 is stored in platelets and maintains vascular integrity, and endothelium-derived angiopoietin-2 promotes vascular leakage. We determined angiopoietin-1 and angiopoietin-2 levels in a cohort of children in Indonesia with DHF/DSS and related them to plasma leakage markers. Patients with DHF/DSS had reduced angiopoietin-1 and increased angiopoietin-2 plasma levels on the day of admission when compared with levels at discharge and in healthy controls. There was an inverse correlation between angiopoietin-1 and markers of plasma leakage and a positive correlation between angiopoietin-2 and markers of plasma leakage. Angiopoietin-1 levels followed the same trend as the soluble platelet activation marker P-selectin and correlated with platelet counts. Dengue-associated thrombocytopenia and endothelial activation are associated with an imbalance in angiopoietin-2: angiopoietin-1 plasma levels. This imbalance may contribute to the transient plasma leakage in DHF/DSS.

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Section: Discussionmentioning

confidence: 90%

Imbalance of Angiopoietin-1 and Angiopoetin-2 in Severe Dengue and Relationship with Thrombocytopenia, Endothelial Activation, and Vascular Stability

Michels¹,

Ven²,

Djamiatun³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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“…Recent 17 studies have shown that heparin inhibits DENV infection of HUVEC and that by 24h pi, the majority 18 of HUVEC can become DENV-antigen positive (Dalrymple and Mackow 2011). To assess this in 19 freshly isolated primary HUVEC, we cultured these cells in the presence or absence of heparin, 20 DENV-infected and measured infectious virus release by plaque assay.…”

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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“…During infection, the virus first attaches to cell surface receptors, such as DC-SIGN (14), heparan sulfate (15,16), and others. After clathrin-mediated endocytosis, the low pH in the endosome induces the E proteins on the virus surface to undergo structural rearrangement from dimers to trimers (9).…”

mentioning

confidence: 99%

Near-Atomic Resolution Cryo-Electron Microscopic Structure of Dengue Serotype 4 Virus

Kostyuchenko

Chew

et al. 2014

J Virol

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Dengue virus (DENV), a mosquito-borne virus, is responsible for millions of cases of infections worldwide. There are four DENV serotypes (DENV1 to -4). After a primary DENV infection, the antibodies elicited confer lifetime protection against that DENV serotype. However, in a secondary infection with another serotype, the preexisting antibodies may cause antibody-dependent enhancement (ADE) of infection of macrophage cells, leading to the development of the more severe form of disease, dengue hemorrhagic fever. Thus, a safe vaccine should stimulate protection against all dengue serotypes simultaneously. To facilitate the development of a vaccine, good knowledge of different DENV serotype structures is crucial. Structures of DENV1 and DENV2 had been solved previously. Here we present a near-atomic resolution cryo-electron microscopy (cryo-EM) structure of mature DENV4. Comparison of the DENV4 structure with similar-resolution cryo-EM structures of DENV1 and DENV2 showed differences in surface charge distribution, which may explain their differences in binding to cellular receptors, such as heparin. Also, observed variations in amino acid residues involved in interactions between envelope and membrane proteins on the virus surface correlate with their ability to undergo structural changes at higher temperatures.

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Productive Dengue Virus Infection of Human Endothelial Cells Is Directed by Heparan Sulfate-Containing Proteoglycan Receptors

Cited by 108 publications

References 81 publications

Imbalance of Angiopoietin-1 and Angiopoetin-2 in Severe Dengue and Relationship with Thrombocytopenia, Endothelial Activation, and Vascular Stability

Imbalance of Angiopoietin-1 and Angiopoetin-2 in Severe Dengue and Relationship with Thrombocytopenia, Endothelial Activation, and Vascular Stability

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

Near-Atomic Resolution Cryo-Electron Microscopic Structure of Dengue Serotype 4 Virus

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