The Role of Autophagy-Mediated Dengue Virus Antibody-Dependent Enhancement Infection of THP-1 Cells

Intervirology ◽  
2020 ◽  
Vol 63 (1-6) ◽  
pp. 57-65
Author(s):  
Liming Jiang ◽  
Qiangming Sun
Keyword(s):  
Dengue Virus ◽  
Dengue Infection ◽  
Denv Infection ◽  
Inhibitory Effect ◽  
Severe Dengue ◽  
Heat Map ◽  
Antibody Dependent Enhancement ◽  
Transmission Electron ◽  
Underlying Mechanisms

<b><i>Background:</i></b> Antibody-dependent enhancement (ADE) of dengue virus (DENV) infection is identified as the main risk factor of severe dengue diseases. The underlying mechanisms leading to severe dengue fever remain unclear. <b><i>Methods:</i></b> THP-1 cells were treated with an autophagy inducer (rapamycin) or inhibitor (3-methyladenine [3-MA]) and infected with DENV and DENV-ADE. In order to investigate the expression profile of autophagy-related genes in DENV-ADE and DENV direct infection of THP-1 cells, the PCR array including 84 autophagy-related genes was selected to detect the expression of related genes, and then heat map and clustergram were established by analysis software to compare the expression differences of these genes between the DENV-ADE and DENV direct infection. <b><i>Results:</i></b> Autophagy-inducing complex related genes ATG5 and ATG12 were upregulated, and autophagosomes were also observed by transmission electron microscopy among DENV-ADE- and DENV-infected THP-1 cells, which indicated that autophagy was involved in dengue infection. The results show that 3-MA has a significant inhibitory effect on ATG12 in THP-1 cells; on the contrary, the expression of ATG12 was upreg­ulated in THP-1 cells that were treated with rapamycin. The autophagy-related genes ESR1, INS, BNIP3, FAS, TGM2, ATG9B, and DAPK1 exhibited significant differences between DENV-ADE and DENV direct infection groups. <b><i>Conclusion:</i></b> In the present study, an additional mechanism of autophagy was inhibited by the autophagy inhibitor (3-MA) in DENV- and DENV-ADE-infected THP-1 cells. Our finding provided a clear link between autophagy and antibody-enhanced infection of DENV.

scholarly journals Down Regulation Of IL-1β Secretion By Tgf-β1 In Macrophages Infected With Dengue Virus

2021 ◽  
Author(s):  
Brenda Ramírez-Aguero ◽  
Javier Serrato-Salas ◽  
José Luis Montiel-Hernández ◽  
Judith González-Christen
Keyword(s):  
Immune Response ◽  
Dengue Virus ◽  
Inflammatory Cytokines ◽  
Denv Infection ◽  
Inhibitory Effect ◽  
Microvascular Endothelium ◽  
Infected Cells ◽  
Tgf Β1 ◽  
Pro Inflammatory Cytokines

AbstractSeveral pathogenic mechanisms have been linked to the severity of dengue virus infection, like viral cytotoxicity, underlying host genetics and comorbidities such as diabetes and dyslipidemia. It has been observed that patients with severe manifestations develop an uncontrolled immune response, with an increase in pro-inflammatory cytokines such as TNF, IL-1β, IL-8, IL-6 and chemokines that damage the human microvascular endothelium, and also in anti-inflammatory cytokines IL-4, IL-10 and TGF-β1. The role of TGF-β1 on dengue is not clear; few studies have been published, and most of them from patient sera data, with both protective and pathological roles have described. The aim of this study was to evaluate the ability of TGF-β1 to regulate the secretion of IL-1β in macrophages infected by DENV using THP-1 cells treated with recombinant TGF-β1 before or after DENV infection. By RT-PCR we did not observe a difference in IL-1β expression between infected cells pretreated with TGF-β1 and those that were not. However, secretion of IL-1β was reduced only in cells stimulated with TGF-β1 before infection, and not in those treated 2 hours post-infection. TGF-β1 receptor blockage with SB505124 inhibitor, prior to the addition of TGF-β1 and infection, abrogated the inhibitory effect of TGF-β1. Our results suggest that DENV could regulate the function of TGF-β1 on macrophages. This negative regulation of the TGF-β1 pathway could be used by DENV to evade the immune response and could contribute to the immunopathology.

scholarly journals The role of different serotypes and dengue virus concentration in the prognosis of dengue shock syndrome in children

2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Tram Van Ta ◽  
Hai Thanh Tran ◽  
Quyen Nguyen Than Ha ◽  
Xuong Tuyet Nguyen ◽  
Vu Kien Tran ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Dengue Infection ◽  
Dengue Shock Syndrome ◽  
Denv Infection ◽  
Virus Concentration ◽  
Denv Serotypes ◽  
Significant Difference ◽  
Almost All ◽  
The Relationship

Dengue haemorrhagic fever (DHF) is a burden of disease in tropical countries, caused by any one of four-dengue virus (DENV) serotypes (DENV-1 to DENV-4). Although there have been many studies on patients with DHF, many things remain unclear, including the role of DENV serotypes and DENV concentration. The objective of this study was to determine the role of different serotypes and DENV concentration in the prognosis of dengue shock syndrome. This was a prospective cohort study, conducted to show information relating to patients’ conditions, such as hematocrit, platelet, leukocytes, and DENV concentration and the differences between DENV serotypes. The study also expressed the relationship between two groups, DHF without shock and DHF with shock, in terms of immune status, different DENV serotypes, and DENV concentration. Two-hundred and thirty-four patients were serologically confirmed as having a DENV infection. On hospital admission day (fever within 72 hours), results showed that almost all patients had a secondary dengue infection (76.5 %). DENV-1 accounted for the highest number of cases (61.11%), and DENV-4 accounted for the lowest (0.43%). No statistically significant difference was found when comparing the two groups (DHF with shock and DHF without shock) or when comparing the groups of different DENV serotypes. The study concluded that different DENV serotypes or DENV concentration in the first day of hospitalization (fever within 72 hours) cannot be used for prognostic of DSS.

scholarly journals Changes in complement alternative pathway components, factor B and factor H during dengue virus infection in the AG129 mouse

2021 ◽  
Author(s):  
Sheila Cabezas-Falcon ◽  
Aidan J. Norbury ◽  
Jarrod Hulme-Jones ◽  
Sonja Klebe ◽  
Penelope Adamson ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Alternative Pathway ◽  
Severe Disease ◽  
Denv Infection ◽  
Factor H ◽  
Severe Dengue ◽  
Complement Alternative Pathway ◽  
Factor B ◽  
Dengue Disease

The complement alternative pathway (AP) is tightly regulated and changes in two important AP components, factor B (FB) and factor H (FH) are linked to severe dengue in humans. Here, a mouse model of dengue was investigated to define the changes in FB and FH and assess the utility of this model to study the role of the AP in severe dengue. Throughout the period of viremia in the AG129 IFN signalling-deficient mouse, an increase in FB and a decrease in FH was observed following dengue virus (DENV) infection, with the former only seen in a model of more severe disease associated with antibody-dependent enhancement (ADE). Terminal disease was associated with a decrease in FB and FH, with greater changes during ADE, and accompanied by increased C3 degradation consistent with complement activation. In silico analysis of NFκΒ, signal transducer and activator of transcription (STAT) and IFN-driven FB and FH promoter elements to reflect the likely impact of the lack of IFN-responses in AG129 mice, demonstrated that these elements differed markedly between human and mouse, notably with mouse FH lacking NFκΒ and key IFN-stimulated response elements (ISRE), and FB with many more NFκΒ and STAT-responsive elements than human FB. Thus, the AG129 mouse offers utility in demonstrating changes in FB and FH that, similar to humans, are associated with severe disease, but lack predicted important human-specific and IFN-dependent responses of FB and FH to DENV-infection that are likely to regulate the subtleties of the overall AP response during dengue disease in humans.

A simple mathematical model to describe antibody-dependent enhancement in heterologous secondary infection in dengue

2018 ◽  
Vol 36 (4) ◽  
pp. 411-438 ◽  
Author(s):  
Miller Cerón Gómez ◽  
Hyun Mo Yang
Keyword(s):  
Mathematical Model ◽  
Secondary Infection ◽  
Denv Infection ◽  
Severe Dengue ◽  
Asymptotically Stable ◽  
Effective Response ◽  
Antibody Dependent Enhancement ◽  
Secondary Infections ◽  
Initial Stage

Abstract We develop a mathematical model to describe the role of antibody-dependent enhancement (ADE) in heterologous secondary infections, assuming that antibodies specific to primary dengue virus (DENV) infection are being produced by immunological memory. The model has a virus-free equilibrium (VFE) and a unique virus-presence equilibrium (VPE). VFE is asymptotically stable when VPE is unstable; and unstable, otherwise. Additionally, there is an asymptotic attractor (not a fixed point) due to the fact that the model assumes unbounded increase in memory cells. In the analysis of the model, ADE must be accounted in the initial stage of infection (a window of time of few days), period of time elapsed from the heterologous infection until the immune system mounting an effective response against the secondary infection. We apply the results yielded by model to evaluate ADE phenomonon in heterologous DENV infection. We also associate the possible occurrence of severe dengue with huge viremia mediated by ADE phenomenon.

scholarly journals Karakteristik Klinis dan Virologis Penderita Demam Berdarah Dengue di Kota Bandar Lampung

2020 ◽  
Vol 12 (2) ◽  
pp. 85-92
Author(s):  
Nurminha Nurminha ◽  
Tori Rihiantoro ◽  
Mara Ipa
Keyword(s):  
Dengue Virus ◽  
Clinical Symptoms ◽  
Serological Test ◽  
Secondary Infection ◽  
Dengue Infection ◽  
Clinical Manifestations ◽  
Denv Infection ◽  
Severe Dengue ◽  
Virus Serotype ◽  
Degree Of Severity

Abstract. Clinical symptoms of dengue virus (DENV) infection range from asymptomatic mild dengue fever(DF), more severe dengue hemorrhagic fever (DHF) up to dengue shock syndrome. One of the determinantsof dengue infection severity was virus virulence. This study aimed to determine the clinical and virologicalcharacteristics of dengue virus infection patients based on the severity degree. A cross-sectional study wasconducted in RSUD Dr. H. Abdul Moeloek, Lampung Province between July-November 2016 with 56 denguepatients as samples selected using purposive sampling. The serological test was done using a rapiddiagnostic test. Blood samples for DENV serotype identification were examined using reverse-transcriptionpolymerase chain reaction. Classification of DENV infection severity was obtained from the patient’s medicalrecord. The results showed that the most common clinical manifestations were fever, headache, and retroorbitalpain, appearing in all patients from every degree of severity. There were Grade I DHF patients whoexperienced Myalgia (15.6%) and petechiae (22.2%). Laboratory results showed that thrombocytopeniaappeared in every grade, even though 13.3% of grade I patients did not experience it. Secondary infectionwas found in 92.9% of samples, and all DENV serotype can be detected in 39.2%samples: DENV-1 (46.7%),DENV-2 (6.7%), DENV-3 (26.7%), and DENV-4 (20%). This study concluded that the majority of clinicalcharacteristics in DHF patients are in line with the degree of severity, with the bleeding as the dominantmanifestation in patients with grade II-IV. Virological characteristics of DENV-1 are dominant in all patientswith DHF grade I-IV.Keywords: dengue virus, serotype, severity, secondary infection, Bandar Lampung

scholarly journals Dengue virus-infected human monocytes trigger late activation of caspase-1, which mediates pro-inflammatory IL-1β secretion and pyroptosis

2013 ◽  
Vol 94 (10) ◽  
pp. 2215-2220 ◽  
Author(s):  
Ter Yong Tan ◽  
Justin Jang Hann Chu
Keyword(s):  
Dengue Virus ◽  
Severe Disease ◽  
Denv Infection ◽  
Current Evidence ◽  
Severe Dengue ◽  
Late Response ◽  
Human Monocytes ◽  
Caspase 1 ◽  
Underlying Pathogenesis

Dengue virus (DENV) infection affects millions of people annually and has the potential to cause fatal haemorrhagic fever and shock. Although the underlying pathogenesis of severe dengue illness is still unclear, current evidence suggests that severe disease progression has an immunological basis. In this study, we investigated the role of caspase-1 during host–pathogen interactions within DENV-infected human monocytes. Using DENV-infected primary monocytes, we examined caspase-1 at various levels of gene expression and probed for potential immune consequences mediated by caspase-1 such as secretion of pro-inflammatory IL-1β and pyroptotic cell death. We report that DENV-infected monocytes upregulated functional caspase-1 mRNA and pro-caspase-1 activation as a late response to infection. In addition, we found that caspase-1 is responsible for IL-1β secretion and pyroptosis of DENV-infected monocytes. Together, our results show that late caspase-1 activation within DENV-infected monocytes can contribute to pro-inflammatory outcomes that might play a role in dengue immunopathogenesis.

scholarly journals The Role of Apolipoproteins in Dengue Infection: A Review

2021 ◽  
Vol 20 (2) ◽  
Author(s):  
Radzi Ikhsan Ahmad ◽  
Fadzilah Mohd Nor ◽  
Wang Seok Mui ◽  
Thuhairah Hasrah Abdul Rahman
Keyword(s):  
Dengue Virus ◽  
Viral Entry ◽  
Dengue Infection ◽  
Cholesterol Content ◽  
Vital Role ◽  
Severe Dengue ◽  
Cholesterol Levels ◽  
Computer Based ◽  
Virus Replication Cycle

The re-emergence of the dengue virus in recent decades has significantly increased with almost 40%-50% of the world’s population being at risk. Meanwhile, cholesterol and its components, apolipoproteins, were found to play a vital role in dengue infectivity and the development of severe dengue. This review attempts to address the functional importance of cholesterol and related apolipoproteins in dengue virus pathogenesis and to identify the potential utilisation of this relationship in future diagnosis and management of dengue. The literature search was conducted using a computer-based electronic search on dengue infection with cholesterol and human lipoproteins from September 2017 to June 2019 through three main search engines: MEDLINE (OVID), PubMed, and Science Direct using the keywords including Flaviviruses, characteristics of dengue virus, the pathogenesis of dengue, enhancement of dengue, metabolism of cholesterol, cholesterol pathway and human lipoproteins in association with dengue. Dengue virus manipulates lipid raft integrity and utilizes cholesterol components and apolipoproteins for virus internalisation through LDLr and SR-BI receptors. Infectivity of the dengue virus correlated with a decrease in the cholesterol content of the virions. High cholesterol levels in the endoplasmic reticulum promote replication complexes formation of dengue virus. Cholesterol is needed for NS1 secretion which is essential in viral replication, dengue pathogenesis, and host immune evasion. Levels of cholesterol and its related components contributed to the development of severe dengue. The interplay between cholesterol and cellular proteins lead to significant effect in all aspects of the dengue virus replication cycle from viral entry to release.

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 Dengue Virus-Infected Dendritic Cells, but Not Monocytes, Activate Natural Killer Cells through a Contact-Dependent Mechanism Involving Adhesion Molecules

mBio ◽  
2017 ◽  
Vol 8 (4) ◽  
Author(s):  
Vivian Vasconcelos Costa ◽  
Weijian Ye ◽  
Qingfeng Chen ◽  
Mauro Martins Teixeira ◽  
Peter Preiser ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Virus Infection ◽  
Dengue Virus ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cell Activation ◽  
Nk Cell ◽  
Denv Infection ◽  
Ifn Γ

ABSTRACT Natural killer (NK) cells play a protective role against dengue virus (DENV) infection, but the cellular and molecular mechanisms are not fully understood. Using an optimized humanized mouse model, we show that human NK cells, through the secretion of gamma interferon (IFN-γ), are critical in the early defense against DENV infection. Depletion of NK cells or neutralization of IFN-γ leads to increased viremia and more severe thrombocytopenia and liver damage in humanized mice. In vitro studies using autologous human NK cells show that DENV-infected monocyte-derived dendritic cells (MDDCs), but not monocytes, activate NK cells in a contact-dependent manner, resulting in upregulation of CD69 and CD25 and secretion of IFN-γ. Blocking adhesion molecules (LFA-1, DNAM-1, CD2, and 2β4) on NK cells abolishes NK cell activation, IFN-γ secretion, and the control of DENV replication. NK cells activated by infected MDDCs also inhibit DENV infection in monocytes. These findings show the essential role of human NK cells in protection against acute DENV infection in vivo, identify adhesion molecules and dendritic cells required for NK cell activation, and delineate the sequence of events for NK cell activation and protection against DENV infection. IMPORTANCE Dengue is a mosquito-transmitted viral disease with a range of symptoms, from mild fever to life-threatening dengue hemorrhagic fever. The diverse disease manifestation is thought to result from a complex interplay between viral and host factors. Using mice engrafted with a human immune system, we show that human NK cells inhibit virus infection through secretion of the cytokine gamma interferon and reduce disease pathogenesis, including depletion of platelets and liver damage. During a natural infection, DENV initially infects dendritic cells in the skin. We find that NK cells interact with infected dendritic cells through physical contact mediated by adhesion molecules and become activated before they can control virus infection. These results show a critical role of human NK cells in controlling DENV infection in vivo and reveal the sequence of molecular and cellular events that activate NK cells to control dengue virus infection. IMPORTANCE Dengue is a mosquito-transmitted viral disease with a range of symptoms, from mild fever to life-threatening dengue hemorrhagic fever. The diverse disease manifestation is thought to result from a complex interplay between viral and host factors. Using mice engrafted with a human immune system, we show that human NK cells inhibit virus infection through secretion of the cytokine gamma interferon and reduce disease pathogenesis, including depletion of platelets and liver damage. During a natural infection, DENV initially infects dendritic cells in the skin. We find that NK cells interact with infected dendritic cells through physical contact mediated by adhesion molecules and become activated before they can control virus infection. These results show a critical role of human NK cells in controlling DENV infection in vivo and reveal the sequence of molecular and cellular events that activate NK cells to control dengue virus infection.

scholarly journals Simulation Model for Dynamics of Dengue with Innate and Humoral Immune Responses

2018 ◽  
Vol 2018 ◽  
pp. 1-18 ◽  
Author(s):  
S. D. Perera ◽  
S. S. N. Perera
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Dengue Virus ◽  
Dengue Infection ◽  
Asymptomatic Infection ◽  
Severe Dengue ◽  
Viral Kinetics ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Kinetics Of

Dengue virus is a mosquito borne Flavivirus and the most prevalent arbovirus in tropical and subtropical regions around the world. The incidence of dengue has increased drastically over the last few years at an alarming rate. The clinical manifestation of dengue ranges from asymptomatic infection to severe dengue. Even though the viral kinetics of dengue infection is lacking, innate immune response and humoral immune response are thought to play a major role in controlling the virus count. Here, we developed a computer simulation mathematical model including both innate and adaptive immune responses to study the within-host dynamics of dengue virus infection. A sensitivity analysis was carried out to identify key parameters that would contribute towards severe dengue. A detailed stability analysis was carried out to identify relevant range of parameters that contributes to different outcomes of the infection. This study provides a qualitative understanding of the biological factors that can explain the viral kinetics during a dengue infection.

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