Targeting glycolysis reduces infection and dampens inflammation in a host-directed therapy for dengue
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE171290 | GEO | 2021/04/02
REPOSITORIES: GEO
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Project description:Dengue virus (DENV) infects hundreds of millions of people annually, yet there is only a limited knowledge of the host immune response to dengue. Here, we used a systems biological approach to perform a detailed analysis of the innate immune response to DENV infection in the whole blood samples of acutely infected humans in Bangkok, Thailand. Transcriptomic analysis revealed that genes encoding pro-inflammatory mediators and type I IFN related proteins, were associated with high levels of virus during the first few days of infection. Individuals with low or negative viremia at the late stage of fever were enriched with genes associated with pathways involved in cell cycle, proliferation, cell metabolism and translational control. Meta-analysis showed significant enrichment in genes specific for innate cells (monocytes, macrophages and DCs) in the specimens with high VL and enrichment in genes specific for NK cells, CD4+ and CD8+ T cells as well as B cells in specimens with low VL. Furthermore, flow cytometric analysis revealed an expansion in the numbers of CD14+CD16+ monocytes and depletion of CD14dimCD16++ cells and BDCA-1+ myeloid DC in blood. Consistent with this, in a non-human primate model, infection with DENV boosted the numbers of CD14+CD16+ monocytes in the blood and in secondary lymphoid organs. In vitro, freshly isolated blood monocytes infected with DENV up regulated CD16 and mediated robust differentiation of resting B cells to CD27++CD38++ plasmablasts and IgG and IgM secretion. Taken together, these data provide a detailed picture of the innate response to dengue infection in humans, and highlight an unappreciated role for CD14+CD16+ monocytes in promoting the differentiation of plasmablasts and mediating antibody response to DENV. We analyzed whole blood samples from 28 dengue patients (DF n=18, DHF=10) hospitalized at the Siriraj Hospital in Bangkok, Thailand during the season of 2009 The specimens were acquired between days 2 and 9 after onset of symptoms (acute illness), and for 19 patients (DF n=13, DHF=6) also at the convalescence at 4 weeks or later after discharge. Additionally, blood was sampled from 9 healthy, non-infected donors to provide controls for transcriptomic and immunological analysis.
2014-06-27 | E-GEOD-51808 | biostudies-arrayexpress
Project description:Our hypothesis is that dengue induces different innate immune responses in patients with mild respective severe dengue. We further hypothesize that severe dengue infection is a consequence of an over reactive inflammatory response which could be inhibited in an early stage by immune suppressants. We hypothesize that the drugs used in this study induce a down regulated inflammatory response; VP-16 by triggering apoptosis and Rosiglitazone by inhibiting NFkB related cytokine production In-vitro dengue infected U937, transcriptional assessment
2014-04-01 | E-GEOD-28985 | biostudies-arrayexpress
Project description:Analysis of the host response to dengue virus at gene expression level. The hypothesis tested in the present study was that dengue virus triggers and regulate different pathaway with different kinetics controlling the antiviral, the inflammatory and the apoptotic response in primary human DC. Results provide important information of the response to DC to dengue virus showing that antioxidant genes are early stimulated after denv infection reflecting an early production of reactive oxygen species. Interestingely, we demonstrated that ROS production and antiviral and apoptotic responses intersect since chemical inhibition of ROS impairs antiviral and apoptotic responses in these cells. Total RNA obtained from in vitro dengue infected primary human dendritic cells at 0, 6, 12, 18, 24 hours compared to uninfected cells at time 0
2014-12-18 | E-GEOD-58278 | biostudies-arrayexpress
Project description:Dengue virus infection can result in severe symptoms including shock and hemorrhage, but an understanding of the molecular correlates of disease severity is lacking. Bulk transcriptomics on blood samples are difficult to interpret because the blood is composed of different cell types that may react differently to virus infection. Dengue virus RNA can be detected in human plasma, however identifying the cells carrying dengue virus through the bloodstream in vivo has proven challenging. Here we used our recently developed viscRNA-Seq approach to profile transcriptomes of thousands of single blood peripheral mononuclear cells from 6 human subjects with dengue fever and severe dengue, as well as to characterize the cell types associated with dengue virus in the human blood. We found that although no bulk transcriptome marker for severe dengue exists, the expression of MX2 in naive B cells, of CD163 in CD14+/CD16+ monocytes and of other genes in specific cell types is highly predictive for severe dengue. We detected virus-associated cells in the blood of two severe dengue patients with high viral load and discovered the majority of these to be B cells expressing germline IgM or IgD immunoglobulin chains and naive markers but also showing signs of activation and expression of CD69, CXCR4, and other surface receptors. In bystander B cells we detected signs of strong immune activation, parallel hypersomatic evolution and, in one severe degue subject, an anomalously large clone of highly mutated, IgG1 plasmablasts that could be reactive to dengue virus. This study presents a high-resolution molecular exploration into dengue virus infection in humans and can be generalized to any RNA virus.
2018-11-19 | GSE116672 | GEO
Project description:Dengue virus (DENV) infects hundreds of millions of people annually, yet there is only a limited knowledge of the host immune response to dengue. Here, we used a systems biological approach to perform a detailed analysis of the innate immune response to DENV infection in the whole blood samples of acutely infected humans in Bangkok, Thailand. Transcriptomic analysis revealed that genes encoding pro-inflammatory mediators and type I IFN related proteins, were associated with high levels of virus during the first few days of infection. Individuals with low or negative viremia at the late stage of fever were enriched with genes associated with pathways involved in cell cycle, proliferation, cell metabolism and translational control. Meta-analysis showed significant enrichment in genes specific for innate cells (monocytes, macrophages and DCs) in the specimens with high VL and enrichment in genes specific for NK cells, CD4+ and CD8+ T cells as well as B cells in specimens with low VL. Furthermore, flow cytometric analysis revealed an expansion in the numbers of CD14+CD16+ monocytes and depletion of CD14dimCD16++ cells and BDCA-1+ myeloid DC in blood. Consistent with this, in a non-human primate model, infection with DENV boosted the numbers of CD14+CD16+ monocytes in the blood and in secondary lymphoid organs. In vitro, freshly isolated blood monocytes infected with DENV up regulated CD16 and mediated robust differentiation of resting B cells to CD27++CD38++ plasmablasts and IgG and IgM secretion. Taken together, these data provide a detailed picture of the innate response to dengue infection in humans, and highlight an unappreciated role for CD14+CD16+ monocytes in promoting the differentiation of plasmablasts and mediating antibody response to DENV.
2014-06-27 | GSE51808 | GEO
Project description:Human primary monocytes were differentiated for 6days in the presence of M-CSF. The resulting macrophages were infected with dengue virus serotype 2, strain 16681 under the following conditions: Mock, Multiplicity of infection (MOI) 1 without antibodies, MOI 1 with 40ng/mL of irrelevant human antibody, MOI 1 with infection enhancing antibody (40ng/mL of a human monoclonal antibody against dengue), and either MOI 5 or MOI 2.5. Total cell RNA was isolated at 2h post infection or 24h post infection.
2014-12-30 | E-MTAB-3138 | biostudies-arrayexpress
Project description:Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identified pre-vaccination mechanisms predictive of broad antibody responses after immunization with a tetravalent live-attenuated DENV vaccine candidate (Butantan-DV/TV003). Anti-inflammatory pathways including TGF-b signaling expressed by CD68low monocytes and the metabolokines phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were positively correlated with broadly neutralizing Ab responses against DENV. In contrast expression of pro-inflammatory pathways and cytokines (IFN, IL-1) in CD68hi monocytes and primary and secondary bile acids negatively correlated with broad DENVDENV specific Ab responses. Induction of TGF-b and IFNs respectively by PC/PE and bile acids in CD68low and CD68hi monocytes and their impact on viral sensing was confirmed in vitro. We show that the balance between metabolites and pro- or anti-inflammatory innate immune cells drives broad and protective B cell response to the live-attenuated dengue vaccine.
2023-07-27 | GSE209760 | GEO
Project description:Cancer cells display an altered metabolism with increased glycolysis and glucose uptake. Anti-cancer strategies targeting glycolysis through metabolic inhibitors have been considered. The glucose analog 2-deoxyglucose (2DG) is imported into cells and after phosphorylation becomes 2DG-6-phosphate, a toxic by-product that inhibits glycolysis. 2DG has other cellular effects and can induce resistance. Using yeast as a model, we performed an unbiased, mass-spectrometry-based approach to probe the cellular effects of 2DG on the proteome and study resistance mechanisms. We found that two 2DG-6-phosphate phosphatases, Dog1 and Dog2, were induced upon exposure to 2DG and participated in 2DG detoxication. 2DG induced Dog2 by activating several signaling pathways, such as the MAPK (the p38 ortholog Hog1)-based stress-responsive pathway, the unfolded protein response (UPR) triggered by 2DG-induced ER stress, and the MAPK (Slt2)-based cell wall integrity (CWI) pathway. Thus, 2DG-induced interference with cellular signaling rewired the expression of these endogenous phosphatases to promote 2DG resistance. Consequently, loss of the UPR or CWI pathways led to 2DG hypersensitivity. In contrast, DOG2 was transcriptionally repressed by glucose availability through the inhibition of the Snf1/AMPK pathway, and glucose-repression mutants were 2DG-resistant. The characterization and genome resequencing of spontaneous 2DG-resistant mutants revealed that DOG2 overexpression was a common strategy to achieve 2DG resistance. A human Dog2 homolog, HDHD1, also displays 2DG-6-phosphate phosphatase activity in vitro, and its overexpression conferred 2DG resistance in HeLa cells, suggesting potential interference with chemotherapies involving 2DG.
2019-09-09 | PXD014373 | Pride
Project description:Dengue fever is an important tropical illness for which there is currently no virus-specific treatment. To shed light on mechanisms involved in the cellular response to dengue virus (DV), we assessed gene expression changes, using Affymetrix GeneChips (HG-U133A), of infected primary human cells and identified changes common to all cells. The common response genes included a set of 23 genes significantly induced upon DV infection of human umbilical vein endothelial cells (HUVECs), dendritic cells (DCs), monocytes, and B cells (analysis of variance, P < 0.05). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), one of the common response genes, was identified as a key link between type I and type II interferon response genes. We found that DV induces TRAIL expression in immune cells and HUVECs at the mRNA and protein levels. The induction of TRAIL expression by DV was found to be dependent on an intact type I interferon signaling pathway. A significant increase in DV RNA accumulation was observed in anti-TRAIL antibody-treated monocytes, B cells, and HUVECs, and, conversely, a decrease in DV RNA was seen in recombinant TRAIL-treated monocytes. Furthermore, recombinant TRAIL inhibited DV titers in DV-infected DCs by an apoptosis-independent mechanism. These data suggest that TRAIL plays an important role in the antiviral response to DV infection and is a candidate for antiviral interventions against DV. We used Affymetrix microarrays to study the response of human host cells to dengue virus (DV). Experiment Overall Design: For three human cell types, RNA was extracted and hybridized on Affymetrix microarrays. We compared a total of 10 samples. Five were infected in vitro for 48 hours with DV, including HUVECs (n=2), monocytes (n=2), and B-cells (n=1). Five were mock-infected controls of the same cell types and numbers. From these samples, were identified 23 genes that were induced by DV infection in all of the cell types.
2008-06-16 | E-GEOD-9378 | biostudies-arrayexpress
Project description:Clinical symptoms of dengue virus (DENV) infection, the most prevalent arthropod-borne viral disease, range from classical mild dengue fever to severe, life-threatening dengue shock syndrome. However, most DENV infections cause few or no symptoms. Asymptomatic DENV-infected patients provide a unique opportunity to decipher the host immune responses leading to virus elimination without negative impact on an individual’s health. We used an integrated approach of transcriptional profiling and immunological analysis to compare a Cambodian population of strictly asymptomatic viremic individuals with clinical dengue patients. Whereas inflammatory pathways and innate immune response pathways were similar between asymptomatic individuals and clinical dengue patients, expression of proteins related to antigen presentation and subsequent T and B cell activation pathways were differentially regulated, independent of viral load and previous DENV infection history. Feedback mechanisms controlled the immune response in asymptomatic viremic individuals, as demonstrated by increased activation of T cell apoptosis-related pathways and FcγRIIB signaling associated with decreased anti-DENV specific antibody concentrations. Taken together, our data illustrate that symptom-free DENV infection in children is associated with determined by increased activation of the adaptive immune compartment and proper control mechanisms, leading to elimination of viral infection without excessive immune activation, with implications for novel vaccine development strategies
2017-09-05 | GSE100299 | GEO