scholarly journals Elevated Dengue Virus Nonstructural Protein 1 Serum Levels and Altered Toll-Like Receptor 4 Expression, Nitric Oxide, and Tumor Necrosis Factor Alpha Production in Dengue Hemorrhagic Fever Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Denise Maciel Carvalho ◽  
Fernanda Gonçalves Garcia ◽  
Ana Paula Sarreta Terra ◽  
Ana Cristina Lopes Tosta ◽  
Luciana de Almeida Silva ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Clinical Outcomes ◽  
Nonstructural Protein ◽  
Hemorrhagic Fever ◽  
Serum Levels ◽  
Innate Immune ◽  
Necrosis Factor Alpha ◽  
Immune Parameters ◽  
Nonstructural Protein 1 ◽  
Factor Alpha

Background. During dengue virus (DV) infection, monocytes produce tumor necrosis factor alpha (TNF-α) and nitric oxide (NO) which might be critical to immunopathogenesis. Since intensity of DV replication may determine clinical outcomes, it is important to know the effects of viral nonstructural protein 1 (NS1) on innate immune parameters of infected patients. The present study investigates the relationships between dengue virus nonstructural protein 1 (NS1) serum levels and innate immune response (TLR4 expression and TNF-α/NO production) of DV infected patients presenting different clinical outcomes.Methodology/Principal Findings. We evaluated NO, NS1 serum levels (ELISA), TNF-αproduction by peripheral blood mononuclear cells (PBMCs), and TLR4 expression on CD14+cells from 37 dengue patients and 20 healthy controls. Early in infection, increased expression of TLR4 in monocytes of patients with dengue fever (DF) was detected compared to patients with dengue hemorrhagic fever (DHF). Moreover, PBMCs of DHF patients showed higher NS1 and lower NO serum levels during the acute febrile phase and a reduced response to TLR4 stimulation by LPS (with a reduced TNF-αproduction) when compared to DF patients.Conclusions/Significance. During DV infection in humans, some innate immune parameters change, depending on the NS1 serum levels, and phase and severity of the disease which may contribute to development of different clinical outcomes.

scholarly journals Production of a Recombinant Dengue Virus 2 NS5 Protein and Potential Use as a Vaccine Antigen

2016 ◽  
Vol 23 (6) ◽  
pp. 460-469 ◽  
Author(s):  
Rúbens Prince dos Santos Alves ◽  
Lennon Ramos Pereira ◽  
Denicar Lina Nascimento Fabris ◽  
Felipe Scassi Salvador ◽  
Robert Andreata Santos ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dengue Virus ◽  
Nonstructural Protein ◽  
Vaccine Antigen ◽  
Dependent Manner ◽  
Nonstructural Proteins ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Factor Alpha ◽  
Dengue Virus Serotypes

ABSTRACTDengue fever is caused by any of the four known dengue virus serotypes (DENV1 to DENV4) that affect millions of people worldwide, causing a significant number of deaths. There are vaccines based on chimeric viruses, but they still are not in clinical use. Anti-DENV vaccine strategies based on nonstructural proteins are promising alternatives to those based on whole virus or structural proteins. The DENV nonstructural protein 5 (NS5) is the main target of anti-DENV T cell-based immune responses in humans. In this study, we purified a soluble recombinant form of DENV2 NS5 expressed inEscherichia coliat large amounts and high purity after optimization of expression conditions and purification steps. The purified DENV2 NS5 was recognized by serum from DENV1-, DENV2-, DENV3-, or DENV4-infected patients in an epitope-conformation-dependent manner. In addition, immunization of BALB/c mice with NS5 induced high levels of NS5-specific antibodies and expansion of gamma interferon- and tumor necrosis factor alpha-producing T cells. Moreover, mice immunized with purified NS5 were partially protected from lethal challenges with the DENV2 NGC strain and with a clinical isolate (JHA1). These results indicate that the recombinant NS5 protein preserves immunological determinants of the native protein and is a promising vaccine antigen capable of inducing protective immune responses.

scholarly journals Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: Part I - Dengue Virus Tropism, Host Innate Immune Responses, and Subversion of Antiviral Responses

2020 ◽  
Author(s):  
Henry Puerta-Guardo ◽  
Scott B. Biering ◽  
Eva Harris ◽  
Norma Pavia-Ruz ◽  
Gonzalo Vázquez-Prokopec ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Nonstructural Protein ◽  
Secondary Infection ◽  
Hypovolemic Shock ◽  
Clinical Manifestations ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Innate Immune ◽  
Vascular Leak ◽  
Dengue Disease

Dengue is the most prevalent emerging mosquito-borne viral disease, affecting more than 40% of the human population worldwide. Many symptomatic dengue virus (DENV) infections result in a relatively benign disease course known as dengue fever (DF). However, a small proportion of patients develop severe clinical manifestations, englobed in two main categories known as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Secondary infection with any of the four dengue virus serotypes (DENV1, -2, -3, and -4) is a risk factor to develop severe forms of dengue disease. DSS is primarily characterized by sudden and abrupt endothelial dysfunction, resulting in vascular leak and organ impairment, which may progress to hypovolemic shock and death. Severe DENV disease (DHF/DSS) is thought to follow a complex relationship between distinct immunopathogenic processes involving host and viral factors, such as the serotype cross-reactive antibody-dependent enhancement (ADE), the activation of T cells and complement pathways, the phenomenon of the cytokine storm, and the newly described viral toxin activity of the nonstructural protein 1 (NS1), which together play critical roles in inducing vascular leak and virus pathogenesis. In this chapter that is divided in two parts, we will outline the recent advances in our understanding of DENV pathogenesis, highlighting key viral-host interactions and discussing how these interactions may contribute to DENV immunopathology and the development of vascular leak, a hallmark of severe dengue. Part I will address the general features of the DENV complex, including the virus structure and genome, epidemiology, and clinical outcomes, followed by an updated review of the literature describing the host innate immune strategies as well as the viral mechanisms acting against and in favor of the DENV replication cycle and infection.

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 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.

scholarly journals Increased Serum Levels of Tumor Necrosis Factor-Alpha, Resistin, and Visfatin in the Children with Autism Spectrum Disorders: A Case-Control Study

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Mohammad Ali Ghaffari ◽  
Elham Mousavinejad ◽  
Forough Riahi ◽  
Masoumeh Mousavinejad ◽  
Mohammad Reza Afsharmanesh
Keyword(s):  
Autism Spectrum Disorders ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Serum Levels ◽  
Autism Spectrum ◽  
Necrosis Factor Alpha ◽  
Children With Asd ◽  
Factor Alpha ◽  
Spectrum Disorders ◽  
Necrosis Factor

Background. Autism spectrum disorders (ASDs) are complex disorders where the pathogenesis is not fully understood. Several proinflammatory and immunoinflammatory disturbances have been observed in the etiology of ASD. There is, however, limited knowledge on variations of adipokines in ASD. The present study aimed to analyze the serum levels of resistin, visfatin, and tumor necrosis factor-alpha (TNF-α) in children with ASD in relation to body weight, gender, and ASD severity level. Method. In total, 30 children with ASD (mean age: 7.72±2.65 y; range; 4–12 y) and 30 healthy children (mean age: 8.4±2.66 y; range: 4–12 y), including males and females, were matched for age, gender, and body mass index (BMI). Serum samples were collected, and visfatin, resistin, and TNF-α serum levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit. Result. Serum visfatin, resistin, and TNF-α levels in children with ASD were significantly higher than that in the healthy patients (p<0.05). Two significant correlations were found: a correlation between resistin and visfatin with TNF-α in children with ASD (R = 0.8 and R = 0.62, resp.) and a correlation between resistin and visfatin in children with ASD (R = 0.66). Conclusion. Higher TNF-α, resistin, and visfatin levels were found in children with ASD in comparison with controls, suggesting that elevated levels of serum proinflammatory agents may be implicated in the pathophysiology of ASD.

scholarly journals Human Immunodeficiency Virus Infection Alters Tumor Necrosis Factor Alpha Production via Toll-Like Receptor-Dependent Pathways in Alveolar Macrophages and U1 Cells

2008 ◽  
Vol 82 (16) ◽  
pp. 7790-7798 ◽  
Author(s):  
Marlynne Q. Nicol ◽  
Jean-Marie Mathys ◽  
Albertina Pereira ◽  
Kevin Ollington ◽  
Michael H. Ieong ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Innate Immune ◽  
Hiv Positive ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Immunodeficiency Virus ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Human immunodeficiency virus (HIV)-positive persons are predisposed to pulmonary infections, even after receiving effective highly active antiretroviral therapy. The reasons for this are unclear but may involve changes in innate immune function. HIV type 1 infection of macrophages impairs effector functions, including cytokine production. We observed decreased constitutive tumor necrosis factor alpha (TNF-α) concentrations and increased soluble tumor necrosis factor receptor type II (sTNFRII) in bronchoalveolar lavage fluid samples from HIV-positive subjects compared to healthy controls. Moreover, net proinflammatory TNF-α activity, as measured by the TNF-α/sTNFRII ratio, decreased as HIV-related disease progressed, as manifested by decreasing CD4 cell count and increasing HIV RNA (viral load). Since TNF-α is an important component of the innate immune system and is produced upon activation of Toll-like receptor (TLR) pathways, we hypothesized that the mechanism associated with deficient TNF-α production in the lung involved altered TLR expression or a deficit in the TLR signaling cascade. We found decreased Toll-like receptor 1 (TLR1) and TLR4 surface expression in HIV-infected U1 monocytic cells compared to the uninfected parental U937 cell line and decreased TLR message in alveolar macrophages (AMs) from HIV-positive subjects. In addition, stimulation with TLR1/2 ligand (Pam3Cys) or TLR4 ligand (lipopolysaccharide) resulted in decreased intracellular phosphorylated extracellular signal-regulated kinase and subsequent decreased transcription and expression of TNF-α in U1 cells compared to U937 cells. AMs from HIV-positive subjects also showed decreased TNF-α production in response to these TLR2 and TLR4 ligands. We postulate that HIV infection alters expression of TLRs with subsequent changes in mitogen-activated protein kinase signaling and cytokine production that ultimately leads to deficiencies of innate immune responses that predispose HIV-positive subjects to infection.

scholarly journals High Circulating Levels of the Dengue Virus Nonstructural Protein NS1 Early in Dengue Illness Correlate with the Development of Dengue Hemorrhagic Fever

2002 ◽  
Vol 186 (8) ◽  
pp. 1165-1168 ◽  
Author(s):  
Daniel H. Libraty ◽  
Paul R. Young ◽  
Darren Pickering ◽  
Timothy P. Endy ◽  
Siripen Kalayanarooj ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Dengue Hemorrhagic Fever ◽  
Nonstructural Protein ◽  
Hemorrhagic Fever ◽  
Circulating Levels

Establishment and characterization of dengue virus type 2 nonstructural protein 1 specific T cell lines

2010 ◽  
Vol 33 (6) ◽  
pp. e75-e80 ◽  
Author(s):  
Yang Xiao-meng ◽  
Jiang Li-fang ◽  
Tang Yun-xia ◽  
Yin Yue ◽  
Liu Wen-quan ◽  
...  
Keyword(s):  
T Cell ◽  
Dengue Virus ◽  
Cell Lines ◽  
Virus Type ◽  
Nonstructural Protein ◽  
Nonstructural Protein 1 ◽  
T Cell Lines ◽  
Dengue Virus Type 2
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