Amino acid changes in two viral proteins drive attenuation of the yellow fever 17D vaccine
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1151729 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30346932.fastq.gz | Fastqsanger.gz | |||
| SRR30346933.fastq.gz | Fastqsanger.gz | |||
| SRR30346934.fastq.gz | Fastqsanger.gz | |||
| SRR30346935.fastq.gz | Fastqsanger.gz | |||
| SRR30346936.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 107 |
Similar Datasets
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:The molecular basis for the attenuation of the yellow fever 17D vaccine [chimerasYFVs_RNAseq]
| PRJNA1151208 | ENA
Project description:The molecular basis for the attenuation of the yellow fever 17D vaccine [wtYFV_RNAseq]
| PRJNA1151155 | ENA
Project description:The molecular basis for the attenuation of the yellow fever 17D vaccine [SHAPEmap]
| PRJNA1151730 | ENA
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
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:ATAC-seq analysis of human CD8 T cells specific for the NS4B-214 epitope in the Yellow fever vaccine YFV-17D strain
2017-12-13 | GSE101609 | GEO
Project description:Despite the long-standing success of the yellow fever virus (YFV) 17D vaccine, the precise virus and host determinants which confer its virulence attenuation remain incompletely defined. To provide insights, we performed YFV genome-level evolutionary analyses combined with investigations of vaccine hepatotropism. Evolutionary analyses confirmed vaccine-specific mutations are selected against in virulent YFV isolates, with genomic signatures of purifying selection most pronounced in the envelope (E) protein, where vaccine-specific mutations are concentrated. Structural prediction and mapping using Alphafold3 confirmed vaccine-specific mutations form a surface-exposed patch on domain III of the E protein, likely overlapping the flavivirus receptor binding domain. In tissue culture, 17D infections exhibited enhanced cell-to-cell spread and cytolysis compared to virulent YFV strains. In humans, YFV infections cause severe liver damage while vaccination has an excellent safety profile. Consequently, we next investigated whether 17D displays impaired tropism for primary human hepatocytes (PHH) or induces distinct cell-intrinsic responses to virulent strains. Surprisingly, ex vivo infections confirmed robust propagation of both 17D and virulent YFV strains in PHH. RNA-sequencing revealed consistent and shared induction of IFNB and IFNL1-4, modulating gene programs associated with antiviral responses, cellular immunity, chemotaxis and inflammation, cell-death, metabolism and protein translation. Consistent with differences in spreading efficiency, subtle differences in virion production kinetics and the magnitude and tempo of PHH transcriptional responses were observed. Antiviral responses to 17D were activated earlier while responses to virulent YFV were delayed but enhanced. In summary, we confirm the YFV vaccine exhibits comparable hepatotropism to virulent strains and induces virtually identical host responses. Mechanistically, these data suggest that impaired hepatotropism and associated cytopathology are not correlates of 17D’s virulence attenuation, implying unknown barriers to systemic dissemination mitigate viscerotropic spread and associated liver pathology upon vaccination.
2025-08-26 | GSE306280 | GEO