scholarly journals E Protein Domain III Determinants of Yellow Fever Virus 17D Vaccine Strain Enhance Binding to Glycosaminoglycans, Impede Virus Spread, and Attenuate Virulence

2008 ◽  
Vol 82 (12) ◽  
pp. 6024-6033 ◽  
Author(s):  
Eva Lee ◽  
Mario Lobigs
Keyword(s):  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Protein Domain ◽  
Type I ◽  
Wild Type ◽  
E Protein ◽  
Virulence Attenuation ◽  
Domain Iii

ABSTRACT The yellow fever virus (YFV) 17D strain is one of the most effective live vaccines for human use, but the in vivo mechanisms for virulence attenuation of the vaccine and the corresponding molecular determinants remain elusive. The vaccine differs phenotypically from wild-type YFV by the loss of viscerotropism, despite replicative fitness in cell culture, and genetically by 20 amino acid changes predominantly located in the envelope (E) protein. We show that three residues in E protein domain III inhibit spread of 17D in extraneural tissues and attenuate virulence in type I/II interferon-deficient mice. One of these residues (Arg380) is a dominant glycosaminoglycan-binding determinant, which mainly accounts for more rapid in vivo clearance of 17D from the bloodstream in comparison to 17D-derived variants with wild-type-like E protein. While other mutations will account for loss of neurotropism and phenotypic stability, the described impact of E protein domain III changes on virus dissemination and virulence is the first rational explanation for the safety of the 17D vaccine in humans.

scholarly journals Vaccine and Wild-Type Strains of Yellow Fever Virus Engage Distinct Entry Mechanisms and Differentially Stimulate Antiviral Immune Responses

mBio ◽  
2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Maria Dolores Fernandez-Garcia ◽  
Laurent Meertens ◽  
Maxime Chazal ◽  
Mohamed Lamine Hafirassou ◽  
Ophélie Dejarnac ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Virus Entry ◽  
Fever Virus ◽  
Host Cells ◽  
Target Cells ◽  
Wild Type ◽  
E Protein ◽  
Virulence Attenuation ◽  
Molecular Determinants

ABSTRACTThe live attenuated yellow fever virus (YFV) vaccine 17D stands as a “gold standard” for a successful vaccine. 17D was developed empirically by passaging the wild-type Asibi strain in mouse and chicken embryo tissues. Despite its immense success, the molecular determinants for virulence attenuation and immunogenicity of the 17D vaccine are poorly understood. 17D evolved several mutations in its genome, most of which lie within the envelope (E) protein. Given the major role played by the YFV E protein during virus entry, it has been hypothesized that the residues that diverge between the Asibi and 17D E proteins may be key determinants of attenuation. In this study, we define the process of YFV entry into target cells and investigate its implication in the activation of the antiviral cytokine response. We found that Asibi infects host cells exclusively via the classical clathrin-mediated endocytosis, while 17D exploits a clathrin-independent pathway for infectious entry. We demonstrate that the mutations in the 17D E protein acquired during the attenuation process are sufficient to explain the differential entry of Asibi versus 17D. Interestingly, we show that 17D binds to and infects host cells more efficiently than Asibi, which culminates in increased delivery of viral RNA into the cytosol and robust activation of the cytokine-mediated antiviral response. Overall, our study reveals that 17D vaccine and Asibi enter target cells through distinct mechanisms and highlights a link between 17D attenuation, virus entry, and immune activation.IMPORTANCEThe yellow fever virus (YFV) vaccine 17D is one of the safest and most effective live virus vaccines ever developed. The molecular determinants for virulence attenuation and immunogenicity of 17D are poorly understood. 17D was generated by serially passaging the virulent Asibi strain in vertebrate tissues. Here we examined the entry mechanisms engaged by YFV Asibi and the 17D vaccine. We found the two viruses use different entry pathways. We show that the mutations differentiating the Asibi envelope (E) protein from the 17D E protein, which arose during attenuation, are key determinants for the use of these distinct entry routes. Finally, we demonstrate that 17D binds and enters host cells more efficiently than Asibi. This results in a higher uptake of viral RNA into the cytoplasm and consequently a greater cytokine-mediated antiviral response. Overall, our data provide new insights into the biology of YFV infection and the mechanisms of viral attenuation.

NMR assignments of the yellow fever virus envelope protein domain III

2007 ◽  
Vol 1 (1) ◽  
pp. 49-50 ◽  
Author(s):  
David E. Volk ◽  
Sai H. A. Gandham ◽  
Fiona J. May ◽  
Anjenique Anderson ◽  
Alan D. T. Barrett ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Envelope Protein ◽  
Nmr Assignments ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Protein Domain ◽  
Virus Envelope ◽  
Virus Envelope Protein ◽  
Domain Iii

scholarly journals In Silico Approach To Design a B-cell Epitope Based Vaccine Target Against Yellow Fever Virus

2019 ◽  
Vol 35 (1) ◽  
pp. 27-35
Author(s):  
Shamira Tabrejee ◽  
M Mahboob Hossain
Keyword(s):  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Peptide Vaccine ◽  
Cell Epitope ◽  
Epitope Prediction ◽  
Fever Virus ◽  
Young Infants ◽  
E Protein

Yellow fever virus is a prototype member of the Flaviviridae family causing high fever and jaundice. Though YF 17D vaccine is administered to yellow fever patients, however it can produce adverse effects in immunocompromised, older people and young infants. The aim of this study is to design an epitope-based peptide vaccine by targeting envelope (E) protein of Yellow Fever Virus. Thirty sequences of E protein of Yellow Fever Virus strains were retrieved from NCBI database. E protein was found to be mostly conserved among all the sequences with little variability and also was identified as a probable antigen. Different epitope prediction tools predicted 4 common epitopes, 3 of which were found to be antigenic. A peptide VKNPTDTGin E protein was predicted to have surface accessibility which overlaps with the VKNPTDTGHGT epitope.So, the whole VKNPTDTGHGT epitope was taken for further analysis. The VKNPTDTGHGT epitope showed 96.67% conservancy and also possesses flexibility, hydrophilicity and non-toxicity. Therefore, VKNPTDTGHGT can be regarded as a potential vaccine candidate against Yellow fever virus with further in vitro and in vivo validation. Bangladesh J Microbiol, Volume 35 Number 1 June 2018, pp 27-35

scholarly journals Molecular determinants of Yellow Fever Virus pathogenicity in Syrian Golden Hamsters: one mutation away from virulence

2018 ◽  
Author(s):  
Raphaëlle Klitting ◽  
Laura Roth ◽  
Félix A. Rey ◽  
Xavier de Lamballerie
Keyword(s):  
Yellow Fever ◽  
Reverse Genetics ◽  
Yellow Fever Virus ◽  
Virulent Strain ◽  
Fever Virus ◽  
Viral Loads ◽  
Synonymous Mutations ◽  
E Protein ◽  
Α Helix

ABSTRACTYellow fever virus (Flavivirusgenus) is an arthropod-borne pathogen which can infect humans, causing a severe viscerotropic disease with a high mortality rate. Adapted viral strains allow the reproduction of yellow fever disease in hamsters with features similar to the human disease. Here, we used the Infectious Subgenomic Amplicons reverse genetics method to produce an equivalent to the hamster-virulent strain, Yellow FeverAp7, by introducing a set of 4 synonymous and 6 non-synonymous mutations into a single subgenomic amplicon, derived from the sequence of theAsibistrain. The resulting strain, Yellow FeverAp7M, induced a disease similar to that described forAp7in terms of symptoms, weight evolution, viral loads in the liver and lethality. Using the same methodology, we produced mutant strains derived from eitherAp7MorAsibiviruses and investigated the role of each ofAp7Mnon-synonymous mutations in itsin vivophenotype. This allowed identifying key components of the virulence mechanism in hamsters. InAp7Mvirus, the reversion of either E/Q27H or E/D155A mutations, led to an important reduction of both virulence andin vivoreplicative fitness. In addition, the introduction of the single D155AAp7Mmutation within the E protein of theAsibivirus was sufficient to drastically modify its phenotype in hamsters towards both a greater replication efficiency and virulence. Finally, inspection of theAsibistrain E protein structure combined toin vivotesting revealed the importance of an exposed α-helix in domain I, containing residues 154 and 155, forAp7Mvirulence in hamsters.

scholarly journals DNA-immunisation with dengue virus E protein domains I/II, but not domain III, enhances Zika, West Nile and Yellow Fever virus infection

PLoS ONE ◽  
2017 ◽  
Vol 12 (7) ◽  
pp. e0181734 ◽  
Author(s):  
Jose L. Slon Campos ◽  
Monica Poggianella ◽  
Sara Marchese ◽  
Monica Mossenta ◽  
Jyoti Rana ◽  
...  
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Protein Domains ◽  
Fever Virus ◽  
West Nile ◽  
E Protein ◽  
Domain Iii

scholarly journals Structure of yellow fever virus envelope protein domain III

Virology ◽  
2009 ◽  
Vol 394 (1) ◽  
pp. 12-18 ◽  
Author(s):  
David E. Volk ◽  
Fiona J. May ◽  
Sai H.A. Gandham ◽  
Anjenique Anderson ◽  
Jana J. Von Lindern ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Envelope Protein ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Protein Domain ◽  
Virus Envelope ◽  
Virus Envelope Protein ◽  
Domain Iii

scholarly journals Identification of envelope protein epitopes that are important in the attenuation process of wild-type yellow fever virus.

1992 ◽  
Vol 66 (7) ◽  
pp. 4265-4270 ◽  
Author(s):  
B K Sil ◽  
L M Dunster ◽  
T N Ledger ◽  
M R Wills ◽  
P D Minor ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Envelope Protein ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Wild Type

scholarly journals Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo

2019 ◽  
Vol 13 (1) ◽  
pp. e0007072 ◽  
Author(s):  
Caroline S. de Freitas ◽  
Luiza M. Higa ◽  
Carolina Q. Sacramento ◽  
André C. Ferreira ◽  
Patrícia A. Reis ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Fever Virus

scholarly journals Host-Specific NS5 Ubiquitination Determines Yellow Fever Virus Tropism

2019 ◽  
Vol 93 (14) ◽  
Author(s):  
Lisa Miorin ◽  
Maudry Laurent-Rolle ◽  
Giuseppe Pisanelli ◽  
Pierre Hendrick Co ◽  
Randy A. Albrecht ◽  
...  
Keyword(s):  
Animal Models ◽  
Mouse Model ◽  
Yellow Fever ◽  
Zika Virus ◽  
Yellow Fever Virus ◽  
Disease Model ◽  
Fever Virus ◽  
Type I ◽  
Human Pathogens ◽  
Immunocompetent Mouse

ABSTRACT The recent yellow fever virus (YFV) epidemic in Brazil in 2017 and Zika virus (ZIKV) epidemic in 2015 serve to remind us of the importance of flaviviruses as emerging human pathogens. With the current global flavivirus threat, there is an urgent need for antivirals and vaccines to curb the spread of these viruses. However, the lack of suitable animal models limits the research questions that can be answered. A common trait of all flaviviruses studied thus far is their ability to antagonize interferon (IFN) signaling so as to enhance viral replication and dissemination. Previously, we reported that YFV NS5 requires the presence of type I IFN (IFN-α/β) for its engagement with human signal transducer and activator of transcription 2 (hSTAT2). In this manuscript, we report that like the NS5 proteins of ZIKV and dengue virus (DENV), YFV NS5 protein is able to bind hSTAT2 but not murine STAT2 (mSTAT2). Contrary to what has been demonstrated with ZIKV NS5 and DENV NS5, replacing mSTAT2 with hSTAT2 cannot rescue the YFV NS5-STAT2 interaction, as YFV NS5 is also unable to interact with hSTAT2 in murine cells. We show that the IFN-α/β-dependent ubiquitination of YFV NS5 that is required for STAT2 binding in human cells is absent in murine cells. In addition, we demonstrate that mSTAT2 restricts YFV replication in vivo. These data serve as further impetus for the development of an immunocompetent mouse model that can serve as a disease model for multiple flaviviruses. IMPORTANCE Flaviviruses such as yellow fever virus (YFV), Zika virus (ZIKV), and dengue virus (DENV) are important human pathogens. A common flavivirus trait is the antagonism of interferon (IFN) signaling to enhance viral replication and spread. We report that like ZIKV NS5 and DENV NS5, YFV NS5 binds human STAT2 (hSTAT2) but not mouse STAT2 (mSTAT2), a type I IFN (IFN-α/β) pathway component. Additionally, we show that contrary to what has been demonstrated with ZIKV NS5 and DENV NS5, YFV NS5 is unable to interact with hSTAT2 in murine cells. We demonstrate that mSTAT2 restricts YFV replication in mice and that this correlates with a lack of IFN-α/β-induced YFV NS5 ubiquitination in murine cells. The lack of suitable animal models limits flavivirus pathogenesis, vaccine, and drug research. These data serve as further impetus for the development of an immunocompetent mouse model that can serve as a disease model for multiple flaviviruses.

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