Unveiling CNPY3 as an Innate Immune Effector and Therapeutic Target against Dengue Virus
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PROVIDER: PRJNA980150 | ENA |
REPOSITORIES: ENA
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Project description:To explore the molecular mechanism of Cnpy3 in the treatment of DENVs infection, transcriptome analysis was performed on the brains of suckling mice at two time points of DENVs infection after LNP-Cnpy3 treatment.
2023-07-31 | GSE234119 | GEO
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: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
2014-04-01 | GSE28985 | GEO
Project description:Sanofi Pasteur is developing a tetravalent YFV 17D vaccine-based chimeric dengue vaccine (TV CYD), which is currently in clinical phase 3 development. DNA microarrays were used to assess the innate gene signature in human mDCs infected with the four CYDs alone or in combination, with a wild type dengue serotype 3 virus, or with a classically attenuated serotype 3 virus (VDV3) shown to be reactogenic in humans. We observed a very reproducible signature for each of the 4 CYDs, involving stimulation of Type I IFN genes and associated genes, together with genes encoding chemokines and other mediators involved in the initiation of adaptive responses. In contrast, the wt DEN3 virus induced a predominantly inflammatory profile, while VDV3 appeared to induce a blunted response, which may have contributed to its clinical outcome. All oligochip experiments were performed in dye swap. For each experiment, the gene expression profile of infected cells was compared with the corresponding profile of uninfected cells. 2 biologicals replicates were performed for each virus.
2011-01-03 | E-GEOD-22329 | 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
Project description:Sanofi Pasteur is developing a tetravalent YFV 17D vaccine-based chimeric dengue vaccine (TV CYD), which is currently in clinical phase 3 development. DNA microarrays were used to assess the innate gene signature in human mDCs infected with the four CYDs alone or in combination, with a wild type dengue serotype 3 virus, or with a classically attenuated serotype 3 virus (VDV3) shown to be reactogenic in humans. We observed a very reproducible signature for each of the 4 CYDs, involving stimulation of Type I IFN genes and associated genes, together with genes encoding chemokines and other mediators involved in the initiation of adaptive responses. In contrast, the wt DEN3 virus induced a predominantly inflammatory profile, while VDV3 appeared to induce a blunted response, which may have contributed to its clinical outcome.
2011-01-03 | GSE22329 | GEO
Project description:Background Deciphering host responses contributing to dengue shock syndrome (DSS), the life-threatening form of acute viral dengue infections, is required to improve both the differential prognosis and the treatments provided to DSS patients, a challenge for clinicians. Methodology/Principal Findings Based on a prospective study, we analyzed the genome-wide expression profiles of whole blood cells from 48 matched Cambodian children: 19 progressed to DSS while 16 and 13 presented respectively classical dengue fever (DF) or dengue hemorrhagic fever grades I/II (DHF). Using multi-way analysis of variance (ANOVA) and adjustment of p-values to control the False Discovery Rate (FDR<10%), we identified a signature of 2959 genes differentiating DSS patients from both DF and DHF, and showed a strong association of this DSS-gene signature with the dengue disease phenotype. Using a combined approach to analyse the molecular patterns associated with the DSS-gene signature, we provide an integrative overview of the transcriptional responses altered in DSS children. In particular, we show that the transcriptome of DSS children blood cells is characterized by a decreased abundance of transcripts related to T and NK lymphocyte responses and by an increased abundance of anti-inflammatory and repair/remodeling transcripts. We also show that unexpected pro-inflammatory gene patterns at the interface between innate immunity, inflammation and host lipid metabolism, known to play pathogenic roles in acute and chronic inflammatory diseases associated with systemic vascular dysfunction, are transcriptionnally active in the blood cells of DSS children. Conclusions/Significance We provide a global while non exhaustive overview of the molecular mechanisms altered in of DSS children and suggest how they may interact to lead to final vascular homeostasis breakdown. We suggest that some mechanisms identified should be considered putative therapeutic targets or biomarkers of progression to DSS. Whole blood genome-wide expression profiles of Cambodian children (3-15 year old) infected with dengue virus, having different clinical outcomes were compared. The studied cohort included 16 acute dengue fever samples, 13 acute dengue hemorrhagic fever samples and 19 acute dengue shock syndrome samples, classified according to the 1997 WHO criteria and randomised for age, gender, viral serotype and day of blood sampling after onset of fever. Microarray data were normalised using the quantile method. Multi-way ANOVA was used to compared the three clinical groups, at several False Discovery Rate of 10. Unsupervised Hierarchical Clustering (TreeView) showed that DSS patients clustered together (17 out of 19), identifying a gene-signature of DSS. Bio-informatics-based analysis using the demonstration version 7.1 of Ingenuity Pathway Analysis software (IPA; Ingenuity Systems, www.ingenuity.com) associated with manual and litterature-based analysis was carried out to identify the most relevant functional processes associated with the identified DSS gene expression profile. This was done by combining most informative canonical pathways identified using IPA, genes having the strongest association with the disease phenotype based on ANOVA analysis, and similarities to molecular patterns altered in other systemic inflammatory processes associated with endothelial dysfunction.
2010-07-21 | E-GEOD-17924 | biostudies-arrayexpress
Project description:Background: Dengue virus (DENV) infection has a global impact on public health. The clinical outcomes (of DENV) can vary from a flu-like illness called dengue fever (DF), to a more severe form, known as dengue hemorrhagic fever (DHF). The underlying innate immune mechanisms leading to protective or detrimental outcomes have not been fully elucidated. Helper innate lymphoid cells (hILCs), an innate lymphocyte recently discovered, functionally resemble T-helper cells and are important in inflammation and homeostasis. However, the role of hILCs in DENV infection had been unexplored. Methods: We performed flow cytometry to investigate the frequency and phenotype of hILCs in peripheral blood mononuclear cells from DENV-infected patients of different disease severities (DF and DHF), and at different phases (febrile and convalescence) of infection. Intracellular cytokine staining of hILCs from DF and DHF were also evaluated by flow cytometry after ex vivo stimulation. Further, the hILCs were sorted and subjected to transcriptome analysis using RNA sequencing. Differential gene expression analysis was performed to compare the febrile and convalescent phase samples in DF and DHF. Selected differentially expressed genes were then validated by quantitative PCR. Results: Phenotypic analysis showed marked activation of all three hILC subsets during the febrile phase as shown by higher CD69 expression when compared to paired convalescent samples, although the frequency of hILCs remained unchanged. Upon ex vivo stimulation, hILCs from febrile phase DHF produced significantly higher IFN-g and IL-4 when compared to those of DF. Transcriptomic analysis showed unique hILCs gene expression in DF and DHF, suggesting that divergent functions of hILCs may be associated with different disease severities. Differential gene expression analysis indicated that hILCs function both in cytokine secretion and cytotoxicity during the febrile phase of DENV infection. Conclusions: Helper ILCs are activated in the febrile phase of DENV infection and display unique transcriptomic changes as well as cytokine production that correlate with severity. Targeting hILCs during early innate response to DENV might help shape subsequent immune responses and potentially lessen the disease severity in the future.
2021-06-09 | GSE155672 | GEO
Project description:Background: We report the detailed development of biomarkers to predict the clinical outcome under dengue infection. Transcriptional signatures from purified peripheral blood mononuclear cells were derived from whole-genome gene-expression microarray data and validated by quantitative PCR and tested in independent samples. Methodology/Principal Findings: The study was performed on patients of a well-characterized dengue cohort from Recife, Brazil. The samples analyzed were collected prospectively from acute febrile dengue patients who evolved with different degrees of disease severity, classic dengue fever or dengue hemorrhagic fever (DHF) and compared with similar samples from other non-dengue febrile illnesses. The DHF samples were collected 2-3 days before the presentation of the plasma leakage symptoms. Differentially-expressed genes were selected by univariate statistical tests as well as multivariate classification techniques. The results showed that at early stages of dengue infection, the genes involved in effector mechanisms of innate immune response presented a weaker activation on patients who later developed hemorrhagic fever, whereas the genes involved in apoptosis were expressed in higher levels. Conclusions/Significance: Some of the gene expression signatures displayed estimated accuracy rates of more than 95%, indicating that expression profiling with these signatures may provide a useful means of DHF prognosis at early stages of infection The samples correspond to blood samples from 26 patients from a cohort in Brazil, divided into three classes, DHF, DF, ND, as follows: 18 were confirmed dengue 3, genotype III cases, among which 10 were diagnosed as dengue hemorrhagic fever (DHF) and 8 as classical dengue fever (DF), and 8 control samples (ND) from febrile patients confirmed to be not infected with dengue. None of the DHF patients presented vasculopathy signs and symptoms at the time the samples used in the functional genomic characterization were collected. At the time of collection the patients referred approximately 5 days of disease and the absence of fever was reported two to three days after enrollment. The samples from the DF, DHF and ND patients were matched to avoid significant differences regarding patient age, gender, dengue infection history and days of symptoms among the groups.
2010-09-01 | E-GEOD-18090 | biostudies-arrayexpress
Project description:Background Deciphering host responses contributing to dengue shock syndrome (DSS), the life-threatening form of acute viral dengue infections, is required to improve both the differential prognosis and the treatments provided to DSS patients, a challenge for clinicians. Methodology/Principal Findings Based on a prospective study, we analyzed the genome-wide expression profiles of whole blood cells from 48 matched Cambodian children: 19 progressed to DSS while 16 and 13 presented respectively classical dengue fever (DF) or dengue hemorrhagic fever grades I/II (DHF). Using multi-way analysis of variance (ANOVA) and adjustment of p-values to control the False Discovery Rate (FDR<10%), we identified a signature of 2959 genes differentiating DSS patients from both DF and DHF, and showed a strong association of this DSS-gene signature with the dengue disease phenotype. Using a combined approach to analyse the molecular patterns associated with the DSS-gene signature, we provide an integrative overview of the transcriptional responses altered in DSS children. In particular, we show that the transcriptome of DSS children blood cells is characterized by a decreased abundance of transcripts related to T and NK lymphocyte responses and by an increased abundance of anti-inflammatory and repair/remodeling transcripts. We also show that unexpected pro-inflammatory gene patterns at the interface between innate immunity, inflammation and host lipid metabolism, known to play pathogenic roles in acute and chronic inflammatory diseases associated with systemic vascular dysfunction, are transcriptionnally active in the blood cells of DSS children. Conclusions/Significance We provide a global while non exhaustive overview of the molecular mechanisms altered in of DSS children and suggest how they may interact to lead to final vascular homeostasis breakdown. We suggest that some mechanisms identified should be considered putative therapeutic targets or biomarkers of progression to DSS.
2010-07-21 | GSE17924 | GEO