The transcriptomic landscape of pediatrics with dengue virus infection reveals the severity-dependent immune response
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE196796 | GEO | 2025/02/14
REPOSITORIES: GEO
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Project description:Dengue virus (DENV) infection is a major emerging disease in tropical and subtropical countries and the influence of host genetics during early phases of infection remains to be fully elucidated. Here we use dendritic cells (DCs) and macrophages from healthy individuals to establish inter-individual variability in DENV infection and antibody-mediated enhancement (ADE). We show that host-related factors determine the severity of the infection rate both in DENV-infected DCs and macrophages following ADE. We then correlate the inter-individual variability in infection rates with genome-wide transcript abundance measured by RNA sequencing in DCs following DENV infection. We report 190 host-related transcripts in DCs that correlate markedly with infection rates that form an ubiquitin-mediated antiviral network. Furthermore, these transcripts are enriched for glycolysis, which we show is critical for the early phases of infection. Among virus induced transcripts (i.e. significant correlation only after DENV), we identify DUSP10 as the best indicator of the severity of infection. These results indicate the importance of host genetics in shaping the severity of DENV infection rates in DCs and identify novel potential DENV-susceptibility targets.
2021-02-26 | GSE111330 | GEO
Project description:Dengue virus (DENV) infection is associated with a range of clinical manifestations, from self-limiting dengue fever (DF) to life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Although DENV-specific CD4 T cells are capable of producing inflammatory cytokines and can acquire cytotoxic functions in previously DENV-exposed individuals, much less is known related to DENV-specific CD4 T cells during acute DENV infection and disease. In this study, we set out to characterize the immune signatures of DENV-specific CD4 T cells during acute infection and investigate whether DENV-specific CD4 T cell response differs between DF and DHF. Previous studies suggest that increased IL-10 level in the blood is associated with severe dengue disease. Here we show evidence of DENV-specific IL-10-producing CD4 T cells during acute DENV infection. More specifically, an IL-10+IFN-γ+ double positive (DP) CD4 T cell population was prominent in acute hospitalized DENV cases but disappeared at the convalescent stage. RNA-sequencing analysis revealed that these cells were associated with gene signatures that marginally overlapped with previously identified signatures of cytotoxic CD4 T cells and type 1 regulatory T (Tr1)-like cells. However, the majority of the genes differentially expressed by DP cells were not related to cytotoxic CD4 T cells or Tr1-like cells. These genes include IL-21, IL-22, CD86, CD109, and CCR1, which are involved in T cell activation, function, cytokine signaling, and migration. Notably, the magnitude of DP cell response was higher in DHF than DF, whereas the gene expression profile of DP cells was similar between DF and DHF. Finally, our data show that DENV-specific DP cells are largely homogeneous based on the expression of 31 selected markers. Overall, this study reveals unique phenotypes of virus-specific IL-10/IFN-γ co-producing CD4 cells and indicates that the quantity but not quality of these cells may be positively correlated with dengue disease severity.
2020-01-13 | GSE132367 | GEO
Project description:The ability of many viruses to manipulate the host antiviral immune response often results in complex host-pathogen interactions. In order to study the interaction of dengue virus (DENV) with the Aedes aegypti immune response, we have characterized the DENV infection-responsive transcriptome of the immune-competent A. aegypti cell line Aag2. As in mosquitoes, DENV infection transcriptionally activated the cell line Toll pathway and a variety of cellular physiological systems. Most notably, however, DENV infection down-regulated the expression levels of numerous immune signaling molecules and antimicrobial peptides (AMPs). Functional assays showed that transcriptional induction of AMPs from the Toll and IMD pathways in response to bacterial challenge is impaired in DENV-infected cells. In addition, Escherichia coli, a gram-negative bacteria species, grew better when co-cultured with DENV-infected cells than with uninfected cells, suggesting a decreased production of AMPs from the IMD pathway in virus-infected cells. Pre-stimulation of the cell line with gram-positive bacteria prior to DENV infection had no effect on DENV titers, while pre-stimulation with gram-negative bacteria resulted in an increase in DENV titers. These results indicate that DENV is capable of actively suppressing immune responses in the cells it infects, a phenomenon that may have important consequences for virus transmission and insect physiology. Infected (dengue virus or heat-inactivated dengue virus) vs. naive cells. 3 replicates each.
2011-10-31 | E-GEOD-33274 | biostudies-arrayexpress
Project description:The ability of many viruses to manipulate the host antiviral immune response often results in complex host-pathogen interactions. In order to study the interaction of dengue virus (DENV) with the Aedes aegypti immune response, we have characterized the DENV infection-responsive transcriptome of the immune-competent A. aegypti cell line Aag2. As in mosquitoes, DENV infection transcriptionally activated the cell line Toll pathway and a variety of cellular physiological systems. Most notably, however, DENV infection down-regulated the expression levels of numerous immune signaling molecules and antimicrobial peptides (AMPs). Functional assays showed that transcriptional induction of AMPs from the Toll and IMD pathways in response to bacterial challenge is impaired in DENV-infected cells. In addition, Escherichia coli, a gram-negative bacteria species, grew better when co-cultured with DENV-infected cells than with uninfected cells, suggesting a decreased production of AMPs from the IMD pathway in virus-infected cells. Pre-stimulation of the cell line with gram-positive bacteria prior to DENV infection had no effect on DENV titers, while pre-stimulation with gram-negative bacteria resulted in an increase in DENV titers. These results indicate that DENV is capable of actively suppressing immune responses in the cells it infects, a phenomenon that may have important consequences for virus transmission and insect physiology.
2011-10-31 | GSE33274 | GEO
Project description:Background: Dengue virus (DENV) infection often leads to acute illness lasting 2-7 days with severity ranging from dengue fever (DF) to hemorrhagic fever (DHF) and fatal dengue shock syndrome (DSS). The dynamic changes of host responses on the gene transcription level that accompany DENV infection and differences between DF and DHF cases have been poorly understood, particularly for South American population. Methodology/Principal Findings: Supported by a longitudinal active surveillance program for dengue transmission in Maracay, Venezuela, we conducted a prospective study to investigate host responses in dengue patients. Blood specimens and clinical information were collected on a daily basis from febrile cases confirmed with DENV infection from their first day of enrollment to early defervescence together with one convalescent sample. A total of 49 and 13 study participants were defined as DF and DHF cases respectively based on their clinical and hematological information. Using convalescent specimens as baseline, day-to-day gene expression was evaluated ex vivo in peripheral blood mononuclear cells of the study participants. Two waves of gene expression were detected: the first wave peaked at day 1 from the onset of fever (day 0) then declined at days 3-4; the second wave emerged from day 4 and peaked around day 5-6. Genes associated with innate immune process, including type I interferon signaling, cytokine-mediated signaling, chemotaxis, and antiviral responses, dominated the first wave; whereas genes involved in cell cycle processes, including cell division, mitosis, DNA replication, chromosome, and spindle organization dominated the second wave. Measureable genomic markers predicted early acute, late acute and convalescent phases with 91% accuracy. Gene signatures expressed in early acute phase predicted disease severity (DF vs DHF) with 96% accuracy. Conclusions/Significance: Our study established a dynamic pattern of detailed host immune responses to DENV infection and revealed genomic signatures valuable for diagnostics purposes.
2013-01-26 | GSE43777 | GEO
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 virus (DENV) is a major human pathogen that belongs to the flavivirus genus. Among non-structural viral proteins, NS1 is an enigmatic factor that is exclusively encoded by members of the flavivirus genus within the Flaviviridae family and accomplishes different functions during DENV infection. To gain insight into the molecular and cellular function of NS1 in viral replication, we generated a tagged NS1 DENV replicon and identified the associated host proteins during active viral replication. Replicons are self-replicating flavivirus RNAs containing large in-frame deletions in the structural genes and are useful tools to study translation and RNA amplification of several flaviviruses. To establish a global map of NS1-host protein interactions occurring during DENV replication, we stably expressed a DENV2 replicon encoding NS1 tagged with N-terminal FLAG and HA epitopes (FH-NS1) or the untagged version (WT) in three different human cell lines (Raji, HeLa and HAP1). Interactors of NS1 were identified by AP-MS/MS from these three different cell lines.
2017-11-29 | PXD008120 | Pride
Project description:Background: Dengue virus (DENV) infection often leads to acute illness lasting 2-7 days with severity ranging from dengue fever (DF) to hemorrhagic fever (DHF) and fatal dengue shock syndrome (DSS). The dynamic changes of host responses on the gene transcription level that accompany DENV infection and differences between DF and DHF cases have been poorly understood, particularly for South American population. Methodology/Principal Findings: Supported by a longitudinal active surveillance program for dengue transmission in Maracay, Venezuela, we conducted a prospective study to investigate host responses in dengue patients. Blood specimens and clinical information were collected on a daily basis from febrile cases confirmed with DENV infection from their first day of enrollment to early defervescence together with one convalescent sample. A total of 49 and 13 study participants were defined as DF and DHF cases respectively based on their clinical and hematological information. Using convalescent specimens as baseline, day-to-day gene expression was evaluated ex vivo in peripheral blood mononuclear cells of the study participants. Two waves of gene expression were detected: the first wave peaked at day 1 from the onset of fever (day 0) then declined at days 3-4; the second wave emerged from day 4 and peaked around day 5-6. Genes associated with innate immune process, including type I interferon signaling, cytokine-mediated signaling, chemotaxis, and antiviral responses, dominated the first wave; whereas genes involved in cell cycle processes, including cell division, mitosis, DNA replication, chromosome, and spindle organization dominated the second wave. Measureable genomic markers predicted early acute, late acute and convalescent phases with 91% accuracy. Gene signatures expressed in early acute phase predicted disease severity (DF vs DHF) with 96% accuracy. Conclusions/Significance: Our study established a dynamic pattern of detailed host immune responses to DENV infection and revealed genomic signatures valuable for diagnostics purposes. Total 64 subjects representing 51 DF (dengue fever) and 13 DHF (dengue hemorrhagic fever) cases were used to study gene expression during the course of dengue acute illness. Sample information regarding Patient No., Infecting serotype, fever status (fever days or defervescent (df) days), and disease severity (DF vs DHF) were provided. The date for a sample for gene chip hybridization and image scanning was marked as Scan date. Samples from study subjects were collected once a patient was enrolled. Over 200 samples were collected. Two genechip platforms were used, the HG-focus and HG-U133plus2. A total of 168 samples were assayed on the HG-focus platform, 2 were excluded for further analysis as they failed on quality control (i.e. VFP-0003_G7_DF, VFP-0029_G1_DF samples). A total of 101 samples were assayed on the HG-U133plus2 platform, 4 were excluded for further analysis as they failed on quality control (i.e. VFP_0186_G4_DF, VFP-0213_G3_DF, VFP_0213_G5_DF, VFP_0220_G3_DHF). Data generated by HG-focus platform were used to explore significantly expressed genes in individual Gs, phases, and for prediction analysis for disease phases. Whereas data generated by HG-U133plus2 were first used to assess the reproducibility of results generated by the HG-focus platform. Secondarily, they were used to perform prediction analysis for disease severity. Samples were grouped into stages (G) based on the timepoint when they were collected: G0=day0 (on the day of fever onset); G1=day 1 (one day after fever onset); G2=day2 (two days after fever onset)M-bM-^@M-&until G5; G6=day6-10 (6-10 days after fever onset); G7= convalescent time point (around day 28 after the first sample). Samples were also grouped into early acute (G0-G3), late acute (G4-G6) and convalescent phases (G7). References for the protocols; PMID 12803996 and 20078211
2013-01-26 | E-GEOD-43777 | biostudies-arrayexpress
Project description:We measured fever-day-specific genome-wide transcript abundance patterns in 105 peripheral blood mononuclear cell (PBMC) samples collected from 41 children hospitalized with dengue virus (DENV) infection in Nicaragua, and from 8 healthy controls. DF1 = primary DF; DF2 = secondary DF; DHF = Dengue Hemorrhagic Fever; DSS = Dengue Shock Syndrome. Samples were collected from pediatric patients with DENV infection at the Hospital Infantil Manuel de Jesus Rivera (HIMJR) in Managua, Nicaragua. Enrollment criteria consisted of hospitalized patients younger than 15 years of age whose parents or guardians completed the informed consent process, and for children 6 years and older who provided assent, and who presented with acute febrile illness of less than 7 days duration with one or more of the following symptoms or signs at the time of evaluation: headache, arthralgia, myalgia, retro-orbital pain, positive tourniquet test, petechiae, and signs of bleeding. Children were considered to have dengue if DENV was detected by RT-PCR or by isolation in cell culture, if an IgM ELISA indicated seroconversion between the acute and convalescent sample, and/or if there was a > 4-fold increase in DENV-specific antibodies between the acute and convalescent phase. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood within four hours of collection and stored in Trizol at -80 oC disease_state_design
2013-03-01 | E-GEOD-38246 | biostudies-arrayexpress
Project description:We investigated the roles of IRF-3 and IRF-7 in innate antiviral immunity against dengue virus (DENV). Double-deficient Irf-3-/-7-/- mice infected with the DENV2 strain S221 possessed 1,000-150,000 fold higher levels of viral RNA than wild-type and single-deficient mice 24 hours after infection; however, they remained resistant to lethal infection. IFN-α/β was induced similarly in wild-type and Irf-3-/- mice post DENV infection, whereas in the Irf-7-/- and Irf-3-/-7-/- mice, significantly low levels of IFN-α/β expression was observed within 24 hours post-infection. IFN-stimulated gene (ISG) induction was also delayed in Irf-3-/-7-/- mice relative to wild-type and single-deficient mice. In particular, Cxcl10 and Ifnα2 were rapidly induced independently of both IRF-3 and IRF-7 in the Irf-3-/-7-/- mice with DENV infection. Higher levels of serum IFN-γ, IL-6, CXCL10, IL-8, IL-12 p70, and TNF were also observed in Irf-3-/-7-/- mice 24 hours after infection, at which time point viral titers peaked and started to be cleared. Antibody-mediated blockade experiments revealed that IFN-γ, CXCL10, and CXCR3 function to restrict DENV replication in Irf-3-/-7-/- mice. Additionally, the ISGs Cxcl10, Ifit1, Ifit3, and Mx2 can be induced via an IRF-3- and IRF-7-independent pathway that does not involve IFN-γ signaling for protection against DENV. Collectively, these results demonstrate that IRF-3 and IRF-7 are redundant, albeit IRF-7 plays a more important role than IRF-3 in inducing the initial IFN-α/β response; only the combined actions of IRF-3 and IRF-7 are necessary for efficient control of early DENV infection; and the late, IRF-3- and IRF-7-independent pathway contributes to anti-DENV immunity. To identify the antiviral genes that are controlled by IRF-3 and IRF-7 signaling during DENV infection, we examined a panel of ISG expression in the spleens of wild-type, Irf-3-/-, Irf-7-/- and Irf-3-/-7-/- mice at 12 or 24 hours after DENV infection using a quantitative PCR array kit. The fold changes in expression of 55 genes from infected mice were normalized to that of strain-matched naïve mice.
2013-08-15 | E-GEOD-49871 | biostudies-arrayexpress