interleukin-8 and Severe-Dengue

Considered as major human arbovirosis, dengue occurs in several clinical forms. Some forms can lead to fatal complications such as dengue shock syndrome. This hypovolemic shock cannot be predicted and specific curative treatments are still lacking, and thus management of patients with dengue is difficult. The purpose of this review is to describe state-of-the-art of the knowledge on the pathophysiology of shock syndrome and to highlight the interest of high-content screening methods in translational approaches between research and medicine for investigation of individual response during dengue shock syndrome.

Topics: Biomarkers; Chemokine CCL5; Cytokines; Dengue Virus; Developing Countries; Endothelium, Vascular; Evidence-Based Medicine; Humans; Interleukin-6; Interleukin-8; Population Surveillance; Risk Factors; Severe Dengue; Severity of Illness Index; Tumor Necrosis Factor-alpha

Dengue is the most common mosquito-borne flaviviral infection in the world today. Several factors contribute and act synergistically to cause severe infection. One of these is dysregulated host immunological mediators that cause transient pathophysiology during infection. These mediators act on the endothelium to increase vascular permeability, which leads to plasma leakage compromising hemodynamics and coagulopathy. We conducted a prospective study to explore the expression of pro- and anti-inflammatory cytokines and how they relate to clinical dengue manifestations, by assessing their dynamics through acute dengue infection in adults admitted to the Hospital for Tropical Diseases, Bangkok, Thailand. We performed cytokine analysis at three phases of infection for 96 hospitalized adults together with serotyping of confirmed dengue infection during the outbreaks of 2015 and 2016. The serum concentrations of seven cytokines (interleukin [IL]-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha, and interferon gamma) were measured in duplicate using a commercial kit (Bio-Plex Human Cytokine Assay). In this study, the cytokine profile was suggestive of a T-helper 2 response. Most patients had secondary infection, and the levels of viremia were higher in patients with plasma leakage than those without plasma leakage. In addition, we observed that bleeding and hepatitis were associated with significantly higher levels of IL-8 during the early phases of infection. Furthermore, IL-6 levels in the early phase of infection were also elevated in bleeding patients with plasma leakage. These results suggest that IL-6 and IL-8 may act in synergy to cause bleeding in patients with plasma leakage.

Topics: Adult; Cytokines; Dengue; Female; Hemorrhage; Hepatitis, Viral, Human; Humans; Interferon-gamma; Interleukin-10; Interleukin-4; Interleukin-6; Interleukin-8; Male; Prospective Studies; Severe Dengue; Tumor Necrosis Factor-alpha; Viral Load

Severe dengue pathogenesis is not fully understood, but high levels of proinflammatory cytokines have been associated with dengue disease severity. In this study, the cytokine levels in 171 sera from Mexican patients with primary dengue fever (DF) and dengue haemorrhagic fever (DHF) from dengue virus (DENV) 1 (n = 116) or 2 (n = 55) were compared. DF and DHF were defined according to the patient's clinical condition, the primary infections as indicated by IgG enzymatic immunoassay negative results, and the infecting serotype as assessed by real-time reverse transcription-polymerase chain reaction. Samples were analysed for circulating levels of interleukin (IL)-12p70, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, IL-6, and IL-8 using a commercial cytometric bead array. Significantly higher IFN-γ levels were found in patients with DHF than those with DF. However, significantly higher IL-12p70, TNF-α, and IL-6 levels were associated with DHF only in patients who were infected with DENV2 but not with DENV1. Moreover, patients with DF who were infected with DENV1 showed higher levels of IL-12p70, TNF-α, and IL-6 than patients with DHF early after-fever onset. The IL-8 levels were similar in all cases regardless of the clinical condition or infection serotype. These results suggest that the association between high proinflammatory cytokine levels and dengue disease severity does not always stand, and it once again highlights the complex nature of DHF pathogenesis.

Topics: Cytokines; Dengue; Dengue Virus; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation Mediators; Interferon-gamma; Interleukin-12; Interleukin-6; Interleukin-8; Male; Mexico; Real-Time Polymerase Chain Reaction; Serogroup; Severe Dengue; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

The pathogenesis of severe dengue has not been fully elucidated. The inflammatory response plays a critical role in the outcome of dengue disease.. In this study, we investigated the levels of 17 important inflammation mediators in plasma collected from mild or severe adult dengue patients at different time points to understand the contribution of inflammation to disease severity and to seek experimental evidence to optimize the existing clinical treatment strategies. Patients were simply classified as mild and severe dengue according to the 2009 WHO classification. Plasma was collected on day 3-5, 6-7, 8-10 and 14-17 of illness. Levels of 17 inflammation mediators including TNF-α, IL-1α, IFN-γ, IL-6, IFN-α, MIF, IL-10, IL-1RA, IL-8, IP-10, MCP-1, RANTES, GRO, eotaxin-1, sICAM-1 and sVCAM-1 were determined by a multiplex Luminex® system. Different trends of inflammation mediators throughout the disease were compared between mild and severe patients.. Inflammation mediators including IL-1α, IFN-γ, IL-10, IL-8, IP-10, MCP-1 and sVCAM-1 displayed significant differences on day 8-10 of illness between mild and severe dengue patients. Their concentrations were higher in severe patients than mild ones at the same time points. Moreover, those cytokines decreased gradually in mild patients but not in severe patients.. Our results revealed the coexistence of excessive inflammatory response and slow resolution of inflammation in severe adult dengue patients. Hence suppression and/or pro-resolution of inflammation could be a potential therapeutic approach for treatment of severe dengue.

Topics: Adolescent; Adult; Case-Control Studies; Chemokine CCL11; Chemokine CCL2; Chemokine CCL5; Chemokine CXCL1; Cytokines; Female; Humans; Inflammation; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interferon-alpha; Interferon-gamma; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Interleukin-1alpha; Interleukin-6; Interleukin-8; Intramolecular Oxidoreductases; Macrophage Migration-Inhibitory Factors; Male; Middle Aged; Severe Dengue; Severity of Illness Index; Time Factors; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Young Adult

Dengue virus (DENV) causes self‑limiting dengue fever (DF), severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). It is generally considered that cytokine storm leads to the increased plasma leakage characteristic of DHF/DSS. In the present study, peripheral blood mononuclear cells (PBMCs) were isolated from blood samples of healthy volunteers and infected with DENV serotype 2 (DENV2). Culture supernatants of DENV2‑infected and -uninfected PBMCs were analyzed using a human cytokine array. Between a 6‑12 h post‑infection, levels of CCL5, IL‑6 and IL‑8 were markedly elevated, while those of TNF‑α decreased. Total RNA isolated from these PBMCs was analyzed by human miRNA microarray to identify differentially expressed microRNAs (miRNAs). Quantitative reverse transcription polymerase chain reaction was used to validate 11 upregulated and 4 downregulated miRNAs. Sanger mibase, miRanda and TargetScan were used to identify 261 common predicted genes. Databases were used to identify homologous sequences on mRNAs of putative target genes that may be directly bound by the miRNAs identified. We found that cytokines and epigenetic regulators may be putative target genes of these miRNAs. Using ingenuity pathway analysis, we noted that canonical pathways, including biological regulation, may be modulated by these miRNAs.

Topics: Cells, Cultured; Chemokine CCL5; Computational Biology; Databases, Genetic; Dengue; Dengue Virus; Down-Regulation; Gene Expression Profiling; Humans; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; MicroRNAs; Oligonucleotide Array Sequence Analysis; Severe Dengue; Tumor Necrosis Factor-alpha; Untranslated Regions; Up-Regulation

Dengue fever (DF) is the most prevalent arthropod-borne viral disease of humans. No safe vaccine is available, there is no experimental animal model and no specific treatment (antiviral) for Dengue virus (DV) infection exists. The pathogenic mechanisms of the severe forms of the disease, such as Dengue shock syndrome (DSS) and Dengue haemorrhagic fever (DHF), in which endothelial damage is the pathognomonic sign, are not fully understood. Clinical observations have revealed significant abnormalities in the coagulation and inflammation systems, with increased levels of soluble thrombomodulin (sTM) in the plasma of patients with DHF/DSS (grade III or IV). Blood sTM was proposed as an early predictor of DSS during the febrile stage. However, the role of the DV in endothelial injury during DSS is unclear. Here, we present novel insights into the participation of DV in the downregulation of the thrombomodulin-thrombin-protein C complex formation at the endothelial surface, with a reduction in activated protein C (APC). APC is the most important vasoprotective protein because it downregulates thrombin generation (by the inactivation of procoagulant factors Va and VIIIa) and has anti-inflammatory, antiapoptotic, and barrier protection properties. These biological functions of APC are associated with the endothelial protein C receptor (EPCR) and protease-activated receptor 1 (PAR-1) signalling pathways, which link the coagulation-inflammation responses. We found alterations in the antithrombotic and cytoprotective protein C pathways during DV infection of human endothelial vascular cells, which may explain the vasculopathy observed during DHF/DSS. Clarification of the basic principles that underlie these processes has important implications for the design of new therapeutic strategies for DHF/DSS.

Topics: Animals; Antigens, CD; Apoptosis; Capillary Permeability; Cell Line; Chlorocebus aethiops; Cytoprotection; Dengue Virus; Endothelial Cells; Endothelial Protein C Receptor; Humans; Inflammation Mediators; Interleukin-8; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein C; Receptor, PAR-1; Receptors, Cell Surface; Severe Dengue; Signal Transduction; Thrombin; Thrombomodulin

The host response to dengue virus infection is characterized by the production of numerous cytokines, but the overall picture appears to be complex. It has been suggested that a balance may be involved between protective and pathologic immune responses. This study aimed to define differential immune responses in association with clinical outcomes by gene expression profiling of a selected panel of inflammatory genes in whole blood samples from children with severe dengue infections.. Whole blood mRNA from 56 Indonesian children with severe dengue virus infections was analyzed during early admission and at day -1, 0, 1, and 5-8 after defervescence. Levels were related to baseline levels collected at a 1-month follow-up visit. Processing of mRNA was performed in a single reaction by multiplex ligation-dependent probe amplification, measuring mRNA levels from genes encoding 36 inflammatory proteins and 14 Toll-like receptor (TLR)-associated molecules. The inflammatory gene profiles showed up-regulation during infection of eight genes, including IFNG and IL12A, which indicated an antiviral response. On the contrary, genes associated with the nuclear factor (NF)-kappaB pathway were down-regulated, including NFKB1, NFKB2, TNFR1, IL1B, IL8, and TNFA. Many of these NF-kappaB pathway-related genes, but not IFNG or IL12A, correlated with adverse clinical events such as development of pleural effusion and hemorrhagic manifestations. The TLR profile showed that TLRs were differentially activated during severe dengue infections: increased expression of TLR7 and TLR4R3 was found together with a decreased expression of TLR1, TLR2, TLR4R4, and TLR4 co-factor CD14.. These data show that different immunological pathways are differently expressed and associated with different clinical outcomes in children with severe dengue infections.

Topics: Adolescent; Child; Child, Preschool; Dengue; Dengue Virus; Female; Gene Expression Profiling; Gene Expression Regulation; Humans; Immunity, Innate; Interleukin-12 Subunit p35; Interleukin-8; Male; NF-kappa B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Severe Dengue; Signal Transduction; Toll-Like Receptors

Dengue fever is the most prevalent viral disease transmitted by vectors (Aedes aegypti, Aedes albopictus) in worldwide. More than 100 million cases occur annually with a mortality rate of 5% and no safe vaccine is available. The pathogenesis of Dengue, where host and viral factors participate in the establishment of Dengue haemorrhagic fever (DHF) and Dengue shock syndrome (DSS) remains unresolved. Clinical observations have revealed significant abnormalities in coagulation and inflammation systems, with increased levels of tissue factor (TF) and the chemokine IL-8, correlating with the severity of the disease and implicating damage to endothelial vascular cells (EVC). Here we present novel insights concerning the crosstalk between the regulatory signaling pathways of the coagulation-inflammation processes, during Dengue virus (DV) infection of EVC. We found that DV up-regulates Protease Activated receptor type-1 (inflammation) and TF (coagulation) receptors, via the phosphorylation of p38 and ERK1/2 MAPKs, which favor the activation of NF-kappaB transcription factor. This induces pro-inflammatory (IL-8) or pro-adhesive (VCAM-1) gene expression which may lead to EVC activation. The elucidation of the basic principles that signal these processes has important implications for the design of new therapeutic strategies for DHF/DSS.

Topics: Blood Coagulation; Cells, Cultured; Dengue Virus; Endothelial Cells; Humans; Inflammation; Inflammation Mediators; Interleukin-8; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Prothrombin; Receptor, PAR-1; Severe Dengue; Signal Transduction; Thrombin; Thromboplastin; Time Factors; Vascular Cell Adhesion Molecule-1; Virulence

Dengue virus causes dengue fever, a mild febrile illness, and at times dengue hemorrhagic fever (DHF), a severe illness the pathogenesis of which is not fully understood. Given the crucial roles played by interleukin-8 (IL-8) as a chemoattractant cytokine and in inflammatory processes, levels of circulating IL-8 in the sera and IL-8 mRNA in the peripheral blood mononuclear cells (PBMC) were measured in 99 patients of a recent dengue epidemic that occurred in India in 1996 and in 21 normal healthy controls. Twenty-six of the patients had dengue fever (DF) and the remaining 73 were diagnosed as having different grades of DHF. All the control normal sera were negative for IL-8, so were their PBMC for IL-8 mRNA. Increased levels of IL-8 in the sera and IL-8 mRNA in their PBMC were observed in patients with severe illness of DHF grades III and IV. Only two out of 26 patients of DF and one out of 10 DHF grade I patient were positive for IL-8 and all three deteriorated to DHF grade IV within 24 hr. All six patients of DHF grade IV who died had higher serum level of IL-8 above 200 pg/ml, the highest being 5,568 pg/ml in one patient; the presence of mRNA for IL-8 was very high in all patients. A striking correlation was observed between increased levels of IL-8 and severe DHF, with greater levels in patients with increased grade of the disease and death. These results suggest that IL-8 may have an important role and may be an indicator of increasing severity of the disease and death.

Topics: Adolescent; Adult; Child; Child, Preschool; Dengue; Female; Gene Expression; Humans; India; Infant; Interleukin-8; Male; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Viral; Severe Dengue

Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) are severe complications of secondary dengue virus (DV) infection. Vascular leakage, hemorrhagic diathesis and complement activation are the hallmarks of the disease. The short-lived nature of the plasma leakage syndrome has led to the conclusion that altered permeability is most likely effected by a soluble mediator. In the present study, we show that infection of human endothelial cells with DV induces the transcriptional up-regulation and secretion of RANTES and IL-8 and, in the presence of anti-dengue Abs, the formation of nonlytic complement complexes. Extremely high levels of IL-8 were detected in plasma and pleural fluid samples from patients with DSS. Furthermore, DV infection of endothelial cells in vitro caused apoptosis. Complement activation, chemokine induction, and apoptotic cell death may act in concert to cause the fulminant but short-lived vascular leakage that is characteristic of DHF/DSS.

Topics: Apoptosis; Cell Death; Cell Line; Chemokine CCL5; Chemokines; Complement Activation; Dengue Virus; Endothelium, Vascular; Humans; Interleukin-8; NF-kappa B; Severe Dengue; Transcription, Genetic; Umbilical Cord; Up-Regulation