ATAC-seq analysis of human CD8 T cells specific for the NS4B-214 epitope in the Yellow fever vaccine YFV-17D strain
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE101609 | GEO | 2017/12/13
SECONDARY ACCESSION(S): PRJNA394987
REPOSITORIES: GEO
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Project description:The yellow fever virus 17D (YFV-17D) live attenuated vaccine is considered one of the successful vaccines ever generated associated with high antiviral immunity, yet the signaling mechanisms that drive the response in infected cells are not understood. Here, we provide a molecular understanding of how metabolic stress and innate immune responses are linked to drive type I IFN expression in response to YFV-17D infection. Comparison of YFV-17D replication with its parental virus, YFV-Asibi, and a related dengue virus revealed that IFN expression requires RIG-I-like Receptor signaling through MAVS, as expected. However, YFV-17D uniquely induces mitochondrial respiration and major metabolic perturbations, including hyperactivation of electron transport to fuel ATP synthase. Mitochondrial hyperactivity generates reactive oxygen species (ROS) including peroxynitrite, blocking of which abrogated MAVS oligomerization and IFN expression in non-immune cells without reducing YFV-17D replication. Scavenging ROS in YFV-17D-infected human dendritic cells increased cell viability yet globally prevented expression of IFN signaling pathways. Thus, adaptation of YFV-17D for high growth imparts mitochondrial hyperactivity to meet energy demands, resulting in generation of ROS as the critical messengers that convert a blunted IFN response into maximal activation of innate immunity essential for vaccine effectiveness.
2025-04-05 | GSE293880 | GEO
Project description:We tested the effects of co-infection on vaccine response to YFV-17D. Groups of mice were divided into either Mock infected or Co-infected groups. Mock infected were housed in a biohazard facility and inoculated with PBS. Co-infected were infected sequentially with murine gammaherpesvirus-68, murine cytomegalovirus, influenza WSN, and Heligmosimoides polygyrus. Both mock and co-infected groups were challenged with Yellow Fever virus (YFV-17D). Day 0 is prior to YFV. Days 3, 7, and 21 were timepoints after YFV.
2016-03-22 | E-GEOD-79466 | biostudies-arrayexpress
Project description:Yellow fever virus, a prototypical member of the Flaviviridae family, is a small single-stranded, positive sense enveloped RNA virus causing viscerotropic, frequently fatal disease. Serial passaging of the virulent YFV Asibi strain in the 1930s yielded the YFV17D strain which remains one of the most effective vaccines ever developed. Remarkably, YFV17D and the virulent parental genome differ only by 68 nucleotides leading to 32 amino acid changes. However, it remains largely unknown which of these sequence differences are responsible for attenuation. Here, we demonstrate that while synonymous mutations are highly conserved across pathogenic YFVs they do not contribute to the characteristic host responses elicited by 17D or virulent viruses. Using a highly modular combinatorial genetic approach we identified key genetic elements in the YFV envelope and non-structural 2A (NS2A) proteins that govern the virus’ ability to spread and suppress host responses.. Introducing these mutations into infectious clones of other YFV genomes results in viral attenuation in vitro and in vivo. Collectively, our results define the genetic basis for YFV17D attenuation and highlight a general approach for creating live-attenuated vaccines for other pathogenic viruses.
2025-05-13 | GSE275593 | GEO
Project description:Yellow fever virus, a prototypical member of the Flaviviridae family, is a small single-stranded, positive sense enveloped RNA virus causing viscerotropic, frequently fatal disease. Serial passaging of the virulent YFV Asibi strain in the 1930s yielded the YFV17D strain which remains one of the most effective vaccines ever developed. Remarkably, YFV17D and the virulent parental genome differ only by 68 nucleotides leading to 32 amino acid changes. However, it remains largely unknown which of these sequence differences are responsible for attenuation. Here, we demonstrate that while synonymous mutations are highly conserved across pathogenic YFVs they do not contribute to the characteristic host responses elicited by 17D or virulent viruses. Using a highly modular combinatorial genetic approach we identified key genetic elements in the YFV envelope and non-structural 2A (NS2A) proteins that govern the virus’ ability to spread and suppress host responses.. Introducing these mutations into infectious clones of other YFV genomes results in viral attenuation in vitro and in vivo. Collectively, our results define the genetic basis for YFV17D attenuation and highlight a general approach for creating live-attenuated vaccines for other pathogenic viruses.
2025-05-13 | GSE275508 | GEO
Project description:Yellow fever virus, a prototypical member of the Flaviviridae family, is a small single-stranded, positive sense enveloped RNA virus causing viscerotropic, frequently fatal disease. Serial passaging of the virulent YFV Asibi strain in the 1930s yielded the YFV17D strain which remains one of the most effective vaccines ever developed. Remarkably, YFV17D and the virulent parental genome differ only by 68 nucleotides leading to 32 amino acid changes. However, it remains largely unknown which of these sequence differences are responsible for attenuation. Here, we demonstrate that while synonymous mutations are highly conserved across pathogenic YFVs they do not contribute to the characteristic host responses elicited by 17D or virulent viruses. Using a highly modular combinatorial genetic approach we identified key genetic elements in the YFV envelope and non-structural 2A (NS2A) proteins that govern the virus’ ability to spread and suppress host responses.. Introducing these mutations into infectious clones of other YFV genomes results in viral attenuation in vitro and in vivo. Collectively, our results define the genetic basis for YFV17D attenuation and highlight a general approach for creating live-attenuated vaccines for other pathogenic viruses.
2025-05-13 | GSE275507 | GEO
Project description:Central questions regarding the origin of memory CD8 T cells, their turnover and longevity in vivo are not well-defined in humans. Here, we have used the highly efficacious live yellow fever virus vaccine (YFV-17D) to address these issues in the context of a primary acute viral infection. We interrogated genome-wide CpG methylation of YFV tetramer-specific CD8 T cells. These findings provide a better understanding of how memory CD8 T cells are formed and maintained in humans.
2017-12-13 | GSE75533 | GEO
Project description:We tested the effects of co-infection on vaccine response to YFV-17D.
2016-03-22 | GSE79466 | GEO
Project description:Immune response to infection involves the regulation of numerouse genes in numerous cell types. The number and type of genes that become differentially expressed in response to infection can result in very different pathophysiologic presentations and disease course. Wild type YFV and 17D despite having very few genetic differences result in very different disease outcomes in human and monkey hosts. We used microarrays to detail the global programme of gene expression of Rhesus macaque immune cells responding to both wild type and 17D strains of YFV. We identified distinct classes of gene expression as well as marked differences in differential gene expression between responses to 17D and wild type strains of YFV. Rhesus PBMC were isolated before and on day 3 of either vaccination with 17D or infection with wild type YFV with an n of 3 per group. Total RNA was extracted and hybridized on Affymetrix microarrays.
2014-10-22 | E-GEOD-51972 | biostudies-arrayexpress
Project description:The non-human primate (NHP) model (specifically rhesus and cynomolgus macaques) has facilitated our understanding of the pathogenic mechanisms of yellow fever (YF) disease and allowed evaluation of safety and efficacy of YF-17D vaccines. However, the accuracy of this model in mimicking vaccine-induced immunity in humans remains to be fully determined. We used a system biology approach to compare hematological, biochemical, transcriptomic, innate and antibody-mediated immune responses in cynomolgus macaques and human participants following YF-17D vaccination. Immune response progression in cynomolgus macaques followed a similar course as in adult humans, but with slightly earlier onset. Yellow fever virus neutralizing antibody responses occurred earlier in cynomolgus macaques (by Day 7 [D7]), but titers >10 were reached in both species by D14 post-vaccination and were not significantly different by D28 (PRNT50 titers 3.6 Log vs 3.5 Log in cynomolgus macaques and human participants, respectively; p = 0.821). Changes in neutrophils, NK cells, monocytes, T and B cell frequency were higher in cynomolgus macaques and persisted for four weeks versus less than two weeks in humans. Low levels of systemic inflammatory cytokines (IL-1Ra, IL-8, MIP-1α, IP-10, MCP-1 or VEGF) were detected in either or both species, but with no or only slight changes versus baseline. Similar changes in gene expression profiles were elicited in both species. These included enriched and up-regulated type I IFN-associated viral sensing, antiviral innate response, and dendritic cell activation pathways D3–D7 post-vaccination in both species. Hematological and blood biochemical parameters remained relatively unchanged versus baseline in both species. Low level YF-17D viremia (RNAemia) was transiently detected in some cynomolgus macaques (28% [5/18]) but generally absent in humans (except one participant [5%; 1/20]). Importance: Cynomolgus macaques were confirmed as a valid surrogate model for replicating YF-17D vaccine-induced responses in humans, and suggest a key role for type I IFN.
2024-03-29 | GSE253538 | GEO
Project description:Correlates of immune mediated protection to most viral and cancer vaccines are still unknown. This impedes the development of novel vaccines to incurable diseases such as HIV and cancer. In this study, we have used functional genomics and polychromatic flow cytometry to define the signature of the immune response to the yellow fever (YF) vaccine 17D (YF17D) in a cohort of forty volunteers followed for up to one year after vaccination. We show that immunization with YF17D leads to an integrated immune response that includes several effector arms of innate immunity including complement, the inflammasome and interferons, as well as adaptive immunity as shown by an early T cell response followed by a brisk and variable B cell response. Development of these responses is preceded, as demonstrated in three independent vaccination trials and in a novel in vitro system of primary immune responses (Modular IMmune In vitro Construct (MIMIC) system), by the coordinated up-regulation of transcripts for specific transcription factors including STAT1, IRF7 and ETS2 that are upstream of the different effector arms of the immune response. These results clearly show that the immune response to a strong vaccine is preceded by coordinated induction of masters transcription factors, that lead to the development of a broad, polyfunctional and persistent immune response that integrates all effector cells of the immune system.
2008-12-01 | GSE13699 | GEO