scholarly journals Molecular Mimicry of Human Endothelial Cell Antigen by Autoantibodies to Nonstructural Protein 1 of Dengue Virus

2011 ◽  
Vol 286 (11) ◽  
pp. 9726-9736 ◽  
Author(s):  
I-Ju Liu ◽  
Chien-Yu Chiu ◽  
Yun-Ching Chen ◽  
Han-Chung Wu
Keyword(s):  
Endothelial Cell ◽  
Dengue Virus ◽  
Molecular Mimicry ◽  
Nonstructural Protein ◽  
Human Endothelial Cell ◽  
Cell Antigen ◽  
Nonstructural Protein 1

Proteomic Analysis of Endothelial Cell Autoantigens Recognized by Anti-Dengue Virus Nonstructural Protein 1 Antibodies

2009 ◽  
Vol 234 (1) ◽  
pp. 63-73 ◽  
Author(s):  
Hsien-Jen Cheng ◽  
Chiou-Feng Lin ◽  
Huan-Yao Lei ◽  
Hsiao-Sheng Liu ◽  
Trai-Ming Yeh ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Dengue Virus ◽  
Proteomic Analysis ◽  
Nonstructural Protein ◽  
Nonstructural Protein 1

scholarly journals A Critical Role for Perivascular Cells in Amplifying Vascular Leakage Induced by Dengue Virus Nonstructural Protein 1

mSphere ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Yin P. Cheung ◽  
Valeria Mastrullo ◽  
Davide Maselli ◽  
Teemapron Butsabong ◽  
Paolo Madeddu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Dengue Virus ◽  
Nonstructural Protein ◽  
Critical Role ◽  
Vascular Leakage ◽  
World Health ◽  
Severe Dengue ◽  
Perivascular Cells ◽  
Nonstructural Protein 1

ABSTRACT Dengue is the most prevalent arthropod-borne viral disease affecting humans, with severe dengue typified by potentially fatal microvascular leakage and hypovolemic shock. Blood vessels of the microvasculature are composed of a tubular structure of endothelial cells ensheathed by perivascular cells (pericytes). Pericytes support endothelial cell barrier formation and maintenance through paracrine and contact-mediated signaling and are critical to microvascular integrity. Pericyte dysfunction has been linked to vascular leakage in noncommunicable pathologies such as diabetic retinopathy but has never been linked to infection-related vascular leakage. Dengue vascular leakage has been shown to result in part from the direct action of the secreted dengue virus (DENV) nonstructural protein NS1 on endothelial cells. Using primary human vascular cells, we show here that NS1 also causes pericyte dysfunction and that NS1-induced endothelial hyperpermeability is more pronounced in the presence of pericytes. Notably, NS1 specifically disrupted the ability of pericytes to support endothelial cell function in a three-dimensional (3D) microvascular assay, with no effect on pericyte viability or physiology. These effects are mediated at least in part through contact-independent paracrine signals involved in endothelial barrier maintenance by pericytes. We therefore identify a role for pericytes in amplifying NS1-induced microvascular hyperpermeability in severe dengue and thus show that pericytes can play a critical role in the etiology of an infectious vascular leakage syndrome. These findings open new avenues of research for the development of drugs and diagnostic assays for combating infection-induced vascular leakage, such as severe dengue. IMPORTANCE The World Health Organization considers dengue one of the top 10 global public health problems. There is no specific antiviral therapy to treat dengue virus and no way of predicting which patients will develop potentially fatal severe dengue, typified by vascular leakage and circulatory shock. We show here that perivascular cells (pericytes) amplify the vascular leakage-inducing effects of the dengue viral protein NS1 through contact-independent signaling to endothelial cells. While pericytes are known to contribute to noncommunicable vascular leakage, this is the first time these cells have been implicated in the vascular effects of an infectious disease. Our findings could pave the way for new therapies and diagnostics to combat dengue and potentially other infectious vascular leakage syndromes.

Anti-dengue virus nonstructural protein 1 antibodies contribute to platelet phagocytosis by macrophages

2016 ◽  
Vol 115 (03) ◽  
pp. 646-656 ◽  
Author(s):  
Ya-Ting Chu ◽  
Chiou-Feng Lin ◽  
Chih-Peng Chang ◽  
Trai-Ming Yeh ◽  
Robert Anderson ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Platelet Adhesion ◽  
Molecular Mimicry ◽  
Nonstructural Protein ◽  
Denv Infection ◽  
Dengue Disease ◽  
Nonstructural Protein 1 ◽  
Tnf Α ◽  
Β3 Integrin ◽  
Lines Of Evidence

SummaryThrombocytopenia is an important clinical manifestation of dengue disease. The hypotheses concerning the pathogenesis of thrombocytopenia include decreased production and increased destruction or consumption of platelets. We previously suggested a mechanism of molecular mimicry in which antibodies (Abs) directed against dengue virus (DENV) nonstructural protein 1 (NS1) cross-react with platelets. Furthermore, several lines of evidence show activation of endothelial cells (ECs) and macrophages are related to dengue disease severity. Previous studies also suggested that Ab-opsonised platelets facilitate the engulfment of platelets by macrophages. Here we show that TNF-α-activated ECs upregulate adhesion molecule expression to enhance the binding of platelets and macrophages and lead to anti-DENV NS1 Ab-mediated platelet phagocytosis. We further demonstrate that the interaction between macrophages and TNF-α-activated ECs requires binding of FcγR with the Fc region of platelet-bound anti-DENV NS1 Abs. Importantly, the binding of anti-DENV NS1 Abs to platelets did not interfere with platelet adhesion to ECs. The adhesion molecules ICAM-1 and β3 integrin expressed on ECs as well as the FcγR expressed on macrophages were critical in anti-DENV NS1 Ab-mediated platelet phagocytosis on activated ECs. Moreover, anti-DENV NS1 Abs dramatically enhanced platelet engulfment by macrophages in a murine model of DENV infection. Our study provides evidence for a novel role for anti-DENV NS1 Abs in the pathogenesis of thrombocytopenia in dengue disease by enhancing platelet phagocytosis by macrophages.

scholarly journals Endothelial Cell Apoptosis Induced by Antibodies Against Dengue Virus Nonstructural Protein 1 Via Production of Nitric Oxide

2002 ◽  
Vol 169 (4) ◽  
pp. 2215-2215 ◽  
Author(s):  
Chiou-Feng Lin ◽  
Huan-Yao Lei ◽  
Ai-Li Shiau ◽  
Hsiao-Sheng Liu ◽  
Trai-Ming Yeh ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cell ◽  
Dengue Virus ◽  
Cell Apoptosis ◽  
Nonstructural Protein ◽  
Endothelial Cell Apoptosis ◽  
Nonstructural Protein 1

scholarly journals Correlation Between Serum Levels of Anti-Endothelial Cell Autoantigen and Anti-Dengue Virus Nonstructural Protein 1 Antibodies in Dengue Patients

2015 ◽  
Vol 92 (5) ◽  
pp. 989-995 ◽  
Author(s):  
Hsien-Jen Cheng ◽  
Tzong-Shiann Ho ◽  
Shu-Wen Wan ◽  
Ching-Chuan Liu ◽  
Yee-Shin Lin ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Dengue Virus ◽  
Nonstructural Protein ◽  
Serum Levels ◽  
Nonstructural Protein 1

scholarly journals Endothelial Cell Apoptosis Induced by Antibodies Against Dengue Virus Nonstructural Protein 1 Via Production of Nitric Oxide

2002 ◽  
Vol 169 (2) ◽  
pp. 657-664 ◽  
Author(s):  
Chiou-Feng Lin ◽  
Huan-Yao Lei ◽  
Ai-Li Shiau ◽  
Hsiao-Sheng Liu ◽  
Trai-Ming Yeh ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cell ◽  
Dengue Virus ◽  
Cell Apoptosis ◽  
Nonstructural Protein ◽  
Endothelial Cell Apoptosis ◽  
Nonstructural Protein 1

scholarly journals Potential Phosphorylation of Viral Nonstructural Protein 1 in Dengue Virus Infection

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1393
Author(s):  
Thanyaporn Dechtawewat ◽  
Sittiruk Roytrakul ◽  
Yodying Yingchutrakul ◽  
Sawanya Charoenlappanit ◽  
Bunpote Siridechadilok ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Nonstructural Protein ◽  
Antiviral Drug ◽  
Denv Infection ◽  
Site Directed Mutagenesis ◽  
Phosphorylation Sites ◽  
Post Translational Modification ◽  
Multifunctional Protein ◽  
Nonstructural Protein 1 ◽  
Underlying Mechanisms

Dengue virus (DENV) infection causes a spectrum of dengue diseases that have unclear underlying mechanisms. Nonstructural protein 1 (NS1) is a multifunctional protein of DENV that is involved in DENV infection and dengue pathogenesis. This study investigated the potential post-translational modification of DENV NS1 by phosphorylation following DENV infection. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), 24 potential phosphorylation sites were identified in both cell-associated and extracellular NS1 proteins from three different cell lines infected with DENV. Cell-free kinase assays also demonstrated kinase activity in purified preparations of DENV NS1 proteins. Further studies were conducted to determine the roles of specific phosphorylation sites on NS1 proteins by site-directed mutagenesis with alanine substitution. The T27A and Y32A mutations had a deleterious effect on DENV infectivity. The T29A, T230A, and S233A mutations significantly decreased the production of infectious DENV but did not affect relative levels of intracellular DENV NS1 expression or NS1 secretion. Only the T230A mutation led to a significant reduction of detectable DENV NS1 dimers in virus-infected cells; however, none of the mutations interfered with DENV NS1 oligomeric formation. These findings highlight the importance of DENV NS1 phosphorylation that may pave the way for future target-specific antiviral drug design.

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