scholarly journals Serum IL-18 Is a Potential Biomarker for Predicting Severe Dengue Disease Progression

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Josephine Diony Nanda ◽  
Chiau-Jing Jung ◽  
Rahmat Dani Satria ◽  
Ming-Kai Jhan ◽  
Ting-Jing Shen ◽  
...  
Keyword(s):  
Acute Phase ◽  
Disease Onset ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Severe Dengue ◽  
Dengue Disease ◽  
Potential Biomarker ◽  
Tnf Α ◽  
Principal Finding

Background. Dengue virus (DENV) infection is the most common arboviral disease that affects tropical and subtropical regions. Based on the clinical hallmarks, the different severities of patients range from mild dengue fever (MDF) to severe dengue diseases (SDDs) and include dengue hemorrhagic fever or dengue shock syndrome. These are commonly associated with cytokine release syndrome (CRS). The types and levels of cytokines/chemokines, which are suppressed or enhanced, are varied, indicating CRS’s pathogenic and host defensive effects. Principal Finding. In this study, we created an integrated and precise multiplex panel of cytokine/chemokine assays based on our literature analysis to monitor dengue CRS. A 24-plex panel of cytokines/chemokines was evaluated to measure the plasma levels of targeting factors in dengue patients with an MDF and SDD diagnosis without or with comorbidities. As identified in sixteen kinds of cytokines/chemokines, ten were significantly ( P < 0.05 ) (10/16) increased, one was significantly ( P < 0.01 ) (1/16) decreased, and five were potentially (5/16) altered in all dengue patients ( n = 30 ) in the acute phase of disease onset. Compared to MDF, the levels of IL-8 (CXCL-8) and IL-18 in SDD were markedly ( P < 0.05 ) increased, accompanied by positively increased IL-6 and TNF-α and decreased IFN-γ and RANTES. With comorbidities, SDD significantly ( P < 0.01 ) portrayed elevated IL-18 accompanied by increased IL-6 and decreased IFN-α2 and IL-12. In addition, decreased platelets were significantly ( P < 0.05 ) associated with increased IL-18. Significance. These results demonstrate an efficient panel of dengue cytokine/chemokine assays used to explore the possible level of CRS during the acute phase of disease onset; also, we are the first to report the increase of IL-18 in severe dengue with comorbidity compared to severe dengue without comorbidity and mild dengue.

scholarly journals Cytokine IL-12, Dengue in children: analysis of a unique relationship

2018 ◽  
Vol 5 (3) ◽  
pp. 1109
Author(s):  
Rakesh Manoharan ◽  
Umapathy Pasupathy ◽  
Latha Ravichandran ◽  
Elayaraja Sivaprakasam ◽  
Srinivasan V. ◽  
...  
Keyword(s):  
Clinical Features ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Study Groups ◽  
Denv Infection ◽  
Warning Signs ◽  
Severe Dengue ◽  
Potential Biomarker ◽  
Paediatric Age ◽  
Dengue With Warning Signs

Background: Dengue is a mosquito borne viral infection caused by one of the four serotypes of dengue viruses (DENV1-DENV4). The consequences of DENV infection range from asymptomatic condition, dengue fever (DF), or severe forms, such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The host immune responses have been considered as the major factor responsible for dengue pathogenesis. In this study, the cytokine IL-12 is reviewed for its utility as potential biomarker of severe dengue disease.Methods: 120 children of paediatric age group with either dengue NS1 antigen or dengue IgM positive were included. Cases were classified as uncomplicated dengue (dengue without warning signs) and complicated dengue (dengue with warning signs and severe dengue). Clinical features and IL-12 (ELISA KIT) levels were analyzed in the study population.Results: Analysis of clinical features among the study groups revealed children with complicated dengue had persistent vomiting (95%), abdominal pain (80%), decreased urine output (50%), bleeding manifestations (83.3%), Hepatomegaly (70%) Haemoconcentration with concurrent thrombocytopenia (93.3%), altered coagulation profile (28.3%), ICU stay (54.7%), leukocytosis (15%), leucopoenia (66.6%) normal leucocytes, (18.4%). Analysis of IL-12 levels revealed children with complicated dengue showed significant elevation compared to controls and uncomplicated dengue.Conclusions: In our study IL-12 levels were significantly higher in complicated dengue patients in comparison with uncomplicated dengue patients as well as normal control population.

scholarly journals Decreased Type I Interferon Production by Plasmacytoid Dendritic Cells Contributes to Severe Dengue

2020 ◽  
Vol 11 ◽  
Author(s):  
Vinit Upasani ◽  
Carolina Scagnolari ◽  
Federica Frasca ◽  
Nikaïa Smith ◽  
Vincent Bondet ◽  
...  
Keyword(s):  
Single Molecule ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Type I Interferons ◽  
Severe Dengue ◽  
Type I ◽  
Type I Ifn ◽  
Dengue Disease ◽  
Healthy Donors

The clinical presentation of dengue virus (DENV) infection is variable. Severe complications mainly result from exacerbated immune responses. Type I interferons (IFN-I) are important in antiviral responses and form a crucial link between innate and adaptive immunity. Their contribution to host defense during DENV infection remains under-studied, as direct quantification of IFN-I is challenging. We combined ultra-sensitive single-molecule array (Simoa) digital ELISA with IFN-I gene expression to elucidate the role of IFN-I in a well-characterized cohort of hospitalized Cambodian children undergoing acute DENV infection. Higher concentrations of type I IFN proteins were observed in blood of DENV patients, compared to healthy donors, and correlated with viral load. Stratifying patients for disease severity, we found a decreased expression of IFN-I in patients with a more severe clinical outcome, such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). This was seen in parallel to a correlation between low IFNα protein concentrations and decreased platelet counts. Type I IFNs concentrations were correlated to frequencies of plasmacytoid DCs, not DENV-infected myloid DCs and correlated inversely with neutralizing anti-DENV antibody titers. Hence, type I IFN produced in the acute phase of infection is associated with less severe outcome of dengue disease.

scholarly journals Pathogenesis of Dengue: Dawn of a New Era

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 1353 ◽  
Author(s):  
Scott B. Halstead
Keyword(s):  
Severe Disease ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Severe Dengue ◽  
Structural Protein ◽  
New Era ◽  
Dengue Disease ◽  
Toll Receptor

Dengue virus (DENV) infections of humans were long thought to be self-limited and of low mortality. Beginning in the 1950s, at the time when four different DENVs were discovered, a lethal variant of dengue emerged. Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) initially observed in Southeast Asia now has spread throughout the world. Two risk factors for DHF/DSS are well-established: severe disease occurs during a second heterotypic DENV infection or during a first DENV infection in infants born to dengue-immune mothers. A large number of hypotheses have been proposed to explain severe dengue disease. As discussed, few of them attempt to explain why severe disease occurs under the two different immunological settings. New experimental evidence has demonstrated that DENV non-structural protein 1 (NS1) is toll-receptor 4 agonist that stimulates primary human myeloid cells to produce the same cytokines observed during the course of severe dengue disease. In addition, NS1 directly damages endothelial cells. These observations have been repeated and extended to an in vivo mouse model. The well-established phenomenon, antibody-dependent enhancement of DENV infection in Fc-receptor-bearing cells, should similarly enhance the production of DENV NS1 in humans, providing a unitary mechanism for severe disease in both immunological settings

scholarly journals Maternal Immunity and Vaccination Influence Disease Severity in Progeny in a Novel Mast Cell-Deficient Mouse Model of Severe Dengue

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 900
Author(s):  
Chinmay Kumar Mantri ◽  
Gayathri Soundarajan ◽  
Wilfried A. A. Saron ◽  
Abhay P. S. Rathore ◽  
Sylvie Alonso ◽  
...  
Keyword(s):  
Mouse Model ◽  
Disease Severity ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Severe Dengue ◽  
Type I ◽  
Complex Interactions ◽  
Dependent Model

Sub-neutralizing concentrations of antibodies in dengue infected patients is a major risk factor for the development of dengue hemorrhagic fever and dengue shock syndrome. Here, we describe a mouse model with a deficiency in mast cells (MCs) in addition to a deficiency in Type-I and II IFN receptors for studying dengue virus (DENV) infection. We used this model to understand the influence of MCs in a maternal antibody-dependent model of severe dengue, where offspring born to DENV-immune mothers are challenged with a heterologous DENV serotype. Mice lacking both MCs and IFN receptors were found susceptible to primary DENV infection and showed morbidity and mortality. When these mice were immunized, pups born to DENV-immune mothers were found to be protected for a longer duration from a heterologous DENV challenge. In the absence of MCs and type-I interferon signaling, IFN-γ was found to protect pups born to naïve mothers but had the opposite effect on pups born to DENV-immune mothers. Our results highlight the complex interactions between MCs and IFN-signaling in influencing the role of maternal antibodies in DENV-induced disease severity.

scholarly journals Roles of Macrophage Migration Inhibitory Factor in Dengue Pathogenesis: From Pathogenic Factor to Therapeutic Target

2020 ◽  
Vol 8 (6) ◽  
pp. 891
Author(s):  
Yen-Chung Lai ◽  
Chiao-Hsuan Chao ◽  
Trai-Ming Yeh
Keyword(s):  
Migration Inhibitory Factor ◽  
Therapeutic Target ◽  
Macrophage Migration Inhibitory Factor ◽  
Critical Factor ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Inhibitory Factor ◽  
Severe Dengue ◽  
Macrophage Migration ◽  
Dengue Disease

Dengue virus (DENV) infection is the most prevalent mosquito-borne viral infection and can lead to severe dengue hemorrhagic fever (DHF) and even life-threatening dengue shock syndrome (DSS). Although the cytokine storm has been revealed as a critical factor in dengue disease, the limited understanding of dengue immunopathogenesis hinders the development of effective treatments. Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine that mediates diverse immune responses, and the serum level of MIF positively correlates with disease severity in patients with dengue. MIF is involved in DENV replication and many pathological changes, such as vascular leakage, during DENV infection. In this paper, the pathogenic roles of MIF and the regulation of MIF secretion during DENV infection are reviewed. Furthermore, whether MIF is a potential therapeutic target against DENV infection is also discussed.

scholarly journals Cells in Dengue Virus Infection In Vivo

2010 ◽  
Vol 2010 ◽  
pp. 1-15 ◽  
Author(s):  
Sansanee Noisakran ◽  
Nattawat Onlamoon ◽  
Pucharee Songprakhon ◽  
Hui-Mien Hsiao ◽  
Kulkanya Chokephaibulkit ◽  
...  
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
Emerging Infectious Diseases ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Severe Dengue ◽  
Dengue Virus Infection ◽  
Dengue Disease

Dengue has been recognized as one of the most important vector-borne emerging infectious diseases globally. Though dengue normally causes a self-limiting infection, some patients may develop a life-threatening illness, dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS). The reason why DHF/DSS occurs in certain individuals is unclear. Studies in the endemic regions suggest that the preexisting antibodies are a risk factor for DHF/DSS. Viremia and thrombocytopenia are the key clinical features of dengue virus infection in patients. The amounts of virus circulating in patients are highly correlated with severe dengue disease, DHF/DSS. Also, the disturbance, mainly a transient depression, of hematological cells is a critical clinical finding in acute dengue patients. However, the cells responsible for the dengue viremia are unresolved in spite of the intensive efforts been made. Dengue virus appears to replicate and proliferate in many adapted cell lines, but these in vitro properties are extremely difficult to be reproduced in primary cells or in vivo. This paper summarizes reports on the permissive cells in vitro and in vivo and suggests a hematological cell lineage for dengue virus infection in vivo, with the hope that a new focus will shed light on further understanding of the complexities of dengue disease.

scholarly journals IL-18: The Forgotten Cytokine in Dengue Immunopathogenesis

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Josephine Diony Nanda ◽  
Tzong-Shiann Ho ◽  
Rahmat Dani Satria ◽  
Ming-Kai Jhan ◽  
Yung-Ting Wang ◽  
...  
Keyword(s):  
Severe Disease ◽  
Denv Infection ◽  
High Serum ◽  
Severe Dengue ◽  
Inflammasome Activation ◽  
Dengue Disease ◽  
Inflammatory Stimuli ◽  
Microbial Infections ◽  
Organ Failures ◽  
Cellular Dysfunction

Dengue fever is an infection by the dengue virus (DENV) transmitted by vector mosquitoes. It causes many infections in tropical and subtropical countries every year, thus posing a severe disease threat. Cytokine storms, one condition where many proinflammatory cytokines are mass-produced, might lead to cellular dysfunction in tissue/organ failures and often facilitate severe dengue disease in patients. Interleukin- (IL-) 18, similar to IL-1β, is a proinflammatory cytokine produced during inflammation following inflammasome activation. Inflammatory stimuli, including microbial infections, damage signals, and cytokines, all induce the production of IL-18. High serum IL-18 is remarkably correlated with severely ill dengue patients; however, its possible roles have been less explored. Based on the clinical and basic findings, this review discusses the potential immunopathogenic role of IL-18 when it participates in DENV infection and dengue disease progression based on existing findings and related past studies.

scholarly journals Dengue Virus Targets Nrf2 for NS2B3-Mediated Degradation Leading to Enhanced Oxidative Stress and Viral Replication

2020 ◽  
Vol 94 (24) ◽  
Author(s):  
Matteo Ferrari ◽  
Alessandra Zevini ◽  
Enrico Palermo ◽  
Michela Muscolini ◽  
Magdalini Alexandridi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Dengue Virus ◽  
Redox Homeostasis ◽  
Reactive Oxygen ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Progressive Increase ◽  
Severe Dengue ◽  
Oxygen Species

ABSTRACT Dengue virus (DENV) is a mosquito-borne virus that infects upward of 300 million people annually and has the potential to cause fatal hemorrhagic fever and shock. While the parameters contributing to dengue immunopathogenesis remain unclear, the collapse of redox homeostasis and the damage induced by oxidative stress have been correlated with the development of inflammation and progression toward the more severe forms of disease. In the present study, we demonstrate that the accumulation of reactive oxygen species (ROS) late after DENV infection (>24 hpi) resulted from a disruption in the balance between oxidative stress and the nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant response. The DENV NS2B3 protease complex strategically targeted Nrf2 for degradation in a proteolysis-independent manner; NS2B3 licensed Nrf2 for lysosomal degradation. Impairment of the Nrf2 regulator by the NS2B3 complex inhibited the antioxidant gene network and contributed to the progressive increase in ROS levels, along with increased virus replication and inflammatory or apoptotic gene expression. By 24 hpi, when increased levels of ROS and antiviral proteins were observed, it appeared that the proviral effect of ROS overcame the antiviral effects of the interferon (IFN) response. Overall, these studies demonstrate that DENV infection disrupts the regulatory interplay between DENV-induced stress responses, Nrf2 antioxidant signaling, and the host antiviral immune response, thus exacerbating oxidative stress and inflammation in DENV infection. IMPORTANCE Dengue virus (DENV) is a mosquito-borne pathogen that threatens 2.5 billion people in more than 100 countries annually. Dengue infection induces a spectrum of clinical symptoms, ranging from classical dengue fever to severe dengue hemorrhagic fever or dengue shock syndrome; however, the complexities of DENV immunopathogenesis remain controversial. Previous studies have reported the importance of the transcription factor Nrf2 in the control of redox homeostasis and antiviral/inflammatory or death responses to DENV. Importantly, the production of reactive oxygen species and the subsequent stress response have been linked to the development of inflammation and progression toward the more severe forms of the disease. Here, we demonstrate that DENV uses the NS2B3 protease complex to strategically target Nrf2 for degradation, leading to a progressive increase in oxidative stress, inflammation, and cell death in infected cells. This study underlines the pivotal role of the Nrf2 regulatory network in the context of DENV infection.

scholarly journals Roles for Endothelial Cells in Dengue Virus Infection

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Nadine A. Dalrymple ◽  
Erich R. Mackow
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
Capillary Permeability ◽  
Virus Disease ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Dengue Virus Infection ◽  
Barrier Functions ◽  
Dengue Disease ◽  
Primary Fluid

Dengue viruses cause two severe diseases that alter vascular fluid barrier functions, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The endothelium is the primary fluid barrier of the vasculature and ultimately the effects of dengue virus infection that cause capillary leakage impact endothelial cell (EC) barrier functions. The ability of dengue virus to infect the endothelium provides a direct means for dengue to alter capillary permeability, permit virus replication, and induce responses that recruit immune cells to the endothelium. Recent studies focused on dengue virus infection of primary ECs have demonstrated that ECs are efficiently infected, rapidly produce viral progeny, and elicit immune enhancing cytokine responses that may contribute to pathogenesis. Furthermore, infected ECs have also been implicated in enhancing viremia and immunopathogenesis within murine dengue disease models. Thus dengue-infected ECs have the potential to directly contribute to immune enhancement, capillary permeability, viremia, and immune targeting of the endothelium. These effects implicate responses of the infected endothelium in dengue pathogenesis and rationalize therapeutic targeting of the endothelium and EC responses as a means of reducing the severity of dengue virus disease.

scholarly journals Recent Advances in DENV Receptors

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Shuyu Fang ◽  
Yanhua Wu ◽  
Na Wu ◽  
Jing Zhang ◽  
Jing An
Keyword(s):  
Endothelial Cells ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Infection Risk ◽  
Target Cells ◽  
Virus Binding ◽  
Dengue Disease ◽  
High Infection ◽  
Key Factor ◽  
Serious Disease

Dengue is an old disease caused by the mosquito-borne dengue viruses (DENVs), which have four antigenically distinct serotypes (DENV1–4). Infection by any of them can cause dengue fever (DF) and/or a more serious disease, that is, dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). In recent decades, incidence of dengue disease has increased 30-fold, putting a third to half of the world’s population living in dengue-endemic areas at high infection risk. However, the pathogenesis of the disease is still poorly understood. The virus binding with its host cell is not only a first and critical step in their replication cycle but also a key factor for the pathogenicity. In recent years, there have been significant advances in understanding interactions of DENVs with their target cells such as dendritic cells (DC), macrophages, endothelial cells, and hepatocytes. Although DENVs reportedly attach to a variety of receptors on these cells, consensus DENV receptors have not been defined. In this review, we summarize receptors for DENVs on different cells identified in recent years.

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