Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE280483 | GEO | 2025/05/22
REPOSITORIES: GEO
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Project description:Dengue is a mosquito-borne virus infection affecting half of the world’s population for which therapies are lacking. The role of T and NK-cells in protection/immunopathogenesis remains unclear for dengue for dengue. We performed a longitudinal phenotypic, functional and transcriptional analyses of T and NK-cells in 124 dengue patients using flow cytometry and single-cell RNA-sequencing. We show that T/NK-cell signatures early in infection discriminate patients who will progressdevelop to severe dengue (SD) from those who do not. These signatures are exacerbated in In patients with overweight/obesity these signatures are exacerbated compared to healthy weight patients, supporting their increased susceptibility to SD. In SD, CD4+/CD8+ T-cells and NK-cells display increased co-inhibitory receptor expression and decreased cytotoxic capacity potential compared to non-SD. Using transcriptional and proteomics approaches we demonstrate decreased Furthermore, type-I Interferon signalling is downregulatedresponses in SD, suggesting defective innate immunity virus-sensing mechanisms may underlie NK/T-cell dysfunction.
2025-05-21 | PXD061694 | Pride
Project description:Dengue virus (DENV) causes widespread mosquito-borne infection. While most symptomatic patients experience mild disease, a fraction progresses to severe dengue (SD)--a life-threatening condition whose pathogenesis remains largely unknown. We integrated virus-inclusive single cell RNA-Seq 2 (viscRNA-Seq 2) with functional assays to determine the immunological hallmarks of SD progression in children’s blood. We show that beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell abundance, gene and protein expression and secretion, and cell-cell communications suggesting increased migration and inflammation in SD progressors, yet concurrent: i) impaired interferon responses and antigen presentation, in part DENV-modulated, by antigen presenting cells (APCs) in face of intact uptake; ii) activation, regulation, and exhaustion of effector responses, enhanced IFNγ-responses, and appearance of HLA-DR-expressing NK cells possibly compensating for APCs impairments. These observations reveal the target cells of DENV in human blood and provide insight into SD pathogenesis beyond antibody-mediated enhancement.
2023-01-16 | GSE220969 | GEO
Project description:Dengue is a pan-tropic public health problem. In children, dengue shock syndrome (DSS) is the most common life-threatening complication. Predicting patients who may develop DSS may improve triage and treatment. To this end, we conducted a nested case-control comparison of the early host-transcriptional features in 24 DSS patients and 56 sex-, age-, virus serotype-matched uncomplicated dengue patients. In the first instance we defined the âearly dengueâ profile. The transcriptional signature in acute versus convalescent samples (â¤72hrs post illness-onset) was defined by an over-abundance of interferon-inducible transcripts (31% of the 551 over-abundant transcripts), and canonical gene ontology terms that included response to virus, immune response, innate immune response and inflammatory response. Pathway and network analysis identified STAT1, STAT2, STAT3, IRF7, IRF9, IRF1, CEBPB and SP1 as key transcriptional factors mediating the early response. Strikingly, the only differences in the transcriptional signatures of early DSS and uncomplicated dengue cases was the greater abundance of several neutrophil-associated transcripts in patients who progressed to DSS, a finding supported by higher plasma concentrations of several canonical proteins associated with neutrophil-degranulation (BPI, ELA2, DEF1A). Elevated levels of neutrophil-associated transcripts were independent of the neutrophil count and also the genotype of the infecting virus, as genome-length sequences of DENV-1 (n=15) and DENV-2 (n=3) viruses sampled from DSS patients were phylogenetically indistinguishable from those sampled from uncomplicated dengue patients (32 DENV-1 and 9 DENV-2). Collectively, these data suggest an hitherto unrecognised association between neutrophil activation, pathogenesis and the development of DSS and point to future strategies for guiding prognosis. 112 patients: 80 with uncomplicated dengue, 32 with dengue shock syndrome
2010-10-29 | E-GEOD-25001 | biostudies-arrayexpress
Project description:MicroRNAs have emerged as relevant players in resistance to infection. We aimed to identify miRNAs involved in natural resistance to dengue infection. Two groups of people living in dengue endemic area were classified as susceptible (SD) or resistant (RD) to dengue virus (DENV) infection according to their anti-DENV antibody status. We hypothesized that anti-DENV seronegative individuals may represent a population resistant to DENV infection. The miRNome from monocytes of 7 individuals of each group was assessed upon mock- or DENV-2 infection.Dysregulated miRNAs were chosen as candidates for functional studies.
2025-02-12 | E-MTAB-13628 | 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:The pandemic caused by SARS-CoV-2 is responsible for terrible health devastation with profoundly harmful consequences for the economic, social and political activities of communities on a global scale. Extraordinary efforts have been made by the world scientific community, who, in solidarity, shared knowledge so that effective vaccines could be produced quickly. However, it is still important to study therapies that can reduce the risk, until group immunity is reached, which, globally, will take a time that is still difficult to predict. On the other hand, the immunity time guaranteed by already approved vaccines is still uncertain.
The current study proposes a therapy whose foundation lies in the important role that innate immunity may have, by preventing the disease from progressing to the acute phase that may eventually lead to the patient’s death. Our focus is on NK cells and their relevant role.
Natural killer cells (NK) are considered the primary defense lymphocytes against virus-infected cells. They play a critical role in modulating the immune system. Preliminary studies in COVID-19 patients with severe disease, suggest a reduction in the number and function of NK cells, resulting in decreased clearance of infected and activated cells and unchecked elevation of inflammation markers that damage tissue. SARS-CoV-2 infection distorts the immune response towards a highly inflammatory phenotype. Restoring the effector functions of NK cells has the potential to correct the delicate immune balance needed to effectively overcome SARS-CoV-2 infection.
2022-06-22 | MODEL2202230002 | BioModels
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:Dengue is a pan-tropic public health problem. In children, dengue shock syndrome (DSS) is the most common life-threatening complication. Predicting patients who may develop DSS may improve triage and treatment. To this end, we conducted a nested case-control comparison of the early host-transcriptional features in 24 DSS patients and 56 sex-, age-, virus serotype-matched uncomplicated dengue patients. In the first instance we defined the “early dengue” profile. The transcriptional signature in acute versus convalescent samples (≤72hrs post illness-onset) was defined by an over-abundance of interferon-inducible transcripts (31% of the 551 over-abundant transcripts), and canonical gene ontology terms that included response to virus, immune response, innate immune response and inflammatory response. Pathway and network analysis identified STAT1, STAT2, STAT3, IRF7, IRF9, IRF1, CEBPB and SP1 as key transcriptional factors mediating the early response. Strikingly, the only differences in the transcriptional signatures of early DSS and uncomplicated dengue cases was the greater abundance of several neutrophil-associated transcripts in patients who progressed to DSS, a finding supported by higher plasma concentrations of several canonical proteins associated with neutrophil-degranulation (BPI, ELA2, DEF1A). Elevated levels of neutrophil-associated transcripts were independent of the neutrophil count and also the genotype of the infecting virus, as genome-length sequences of DENV-1 (n=15) and DENV-2 (n=3) viruses sampled from DSS patients were phylogenetically indistinguishable from those sampled from uncomplicated dengue patients (32 DENV-1 and 9 DENV-2). Collectively, these data suggest an hitherto unrecognised association between neutrophil activation, pathogenesis and the development of DSS and point to future strategies for guiding prognosis.
2010-10-29 | GSE25001 | GEO
Project description:Dengue virus is an + strand RNA virus. We have carried our infections of human cells with Dengue and analyzed the translation, replication, and localization of the Dengue RNA. This allowed for clear definition of the life cycle of the Dengue virus inside a host cell. We also assessed the host response to Dengue virus, finding that a large fraction of the translational response is due to Interferon function. Translational and transcriptional analysis of the cellular response to Dengue virus infection
2016-09-01 | E-GEOD-69602 | biostudies-arrayexpress
Project description:Background Dengue virus (DENV) infection causes viral haemorrhagic fever that is characterized by extensive activation of the immune system. The aim of this study is to investigate the kinetics of the transcriptome signature changes during the course of disease and the association of genes in these signatures with clinical parameters. Methodology/principle findings Sequential whole blood samples from DENV infected patients in Jakarta were profiled using affymetrix microarrays, which were analysed using principal component analysis, limma, gene set analysis, and weighted gene co-expression network analysis. We show that time since onset of disease, but not diagnosis, has a large impact on the blood transcriptome of patients with non-severe dengue. Clinical diagnosis (according to the WHO classification) does not associate with differential gene expression. Network analysis however indicated that the clinical markers platelet count, fibrinogen, albumin, IV fluid distributed per day and liver enzymes SGOT and SGPT strongly correlate with gene modules that are enriched for genes involved in the immune response and coagulation. Overall, we see a shift in the transcriptome from immunity and inflammation to repair and recovery during the course of DENV infection. Conclusions/significance Time since onset of disease associates with the shift in transcriptome signatures from immunity and inflammation to cell cycle and repair mechanisms in patients with non-severe dengue. The strong association of time with blood transcriptome changes hampers both the discovery as well as the potential application of biomarkers in dengue. However, we identified gene expression modules that associate with key clinical parameters of dengue that reflect the systemic activity of disease during the course of infection. The expression level of these gene modules may support earlier detection of disease progression as well as clinical management of dengue.
2015-02-28 | E-MTAB-3162 | biostudies-arrayexpress