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

ABSTRACT Previous studies have suggested that α-glucosidase inhibitors such as castanospermine and deoxynojirimycin inhibit dengue virus type 1 infection by disrupting the folding of the structural proteins prM and E, a step crucial to viral secretion. We extend these studies by evaluating the inhibitory activity of castanospermine against a panel of clinically important flaviviruses including all four serotypes of dengue virus, yellow fever virus, and West Nile virus. Using in vitro assays we demonstrated that infections by all serotypes of dengue virus were inhibited by castanospermine. In contrast, yellow fever virus and West Nile virus were partially and almost completely resistant to the effects of the drug, respectively. Castanospermine inhibited dengue virus infection at the level of secretion and infectivity of viral particles. Importantly, castanospermine prevented mortality in a mouse model of dengue virus infection, with doses of 10, 50, and 250 mg/kg of body weight per day being highly effective at promoting survival (P ≤ 0.0001). Correspondingly, castanospermine had no adverse or protective effect on West Nile virus mortality in an analogous mouse model. Overall, our data suggest that castanospermine has a strong antiviral effect on dengue virus infection and warrants further development as a possible treatment in humans.

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Simultaneous detection of Dengue virus, Chikungunya virus, Zika virus, Yellow fever virus and West Nile virus

Journal of Virological Methods ◽

10.1016/j.jviromet.2019.03.014 ◽

2019 ◽

Vol 268 ◽

pp. 53-55 ◽

Cited By ~ 3

Author(s):

José A. Boga ◽

Marta E. Alvarez-Arguelles ◽

Susana Rojo-Alba ◽

Mercedes Rodríguez ◽

María de Oña ◽

...

Keyword(s):

West Nile Virus ◽

Dengue Virus ◽

Yellow Fever ◽

Zika Virus ◽

Chikungunya Virus ◽

Yellow Fever Virus ◽

Simultaneous Detection ◽

Fever Virus ◽

West Nile ◽

Virus Zika

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

Journal of Virology ◽

10.1128/jvi.02509-07 ◽

2008 ◽

Vol 82 (12) ◽

pp. 6024-6033 ◽

Cited By ~ 62

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.

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Modeling mRNA-based vaccine YFV.E1988 against yellow fever virus E-protein using immuno-informatics and reverse vaccinology approach

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2021.2024253 ◽

2022 ◽

pp. 1-22

Author(s):

Nabiha Tasneem Khan ◽

Maliha Afroj Zinnia ◽

Abul Bashar Mir Md. Khademul Islam

Keyword(s):

Yellow Fever ◽

Yellow Fever Virus ◽

Fever Virus ◽

Reverse Vaccinology ◽

E Protein

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Yellow Fever Virus/Dengue-2 Virus and Yellow Fever Virus/Dengue-4 Virus Chimeras: Biological Characterization, Immunogenicity, and Protection against Dengue Encephalitis in the Mouse Model

Journal of Virology ◽

10.1128/jvi.77.6.3655-3668.2003 ◽

2003 ◽

Vol 77 (6) ◽

pp. 3655-3668 ◽

Cited By ~ 33

Author(s):

Thomas J. Chambers ◽

Yan Liang ◽

Deborah A. Droll ◽

Jacob J. Schlesinger ◽

Andrew D. Davidson ◽

...

Keyword(s):

Mouse Model ◽

Dengue Virus ◽

Yellow Fever ◽

Yellow Fever Virus ◽

Fever Virus ◽

E Proteins ◽

Dengue Viruses ◽

Intracerebral Inoculation ◽

Intraperitoneal Route ◽

Chimeric Viruses

ABSTRACT Two yellow fever virus (YFV)/dengue virus chimeras which encode the prM and E proteins of either dengue virus serotype 2 (dengue-2 virus) or dengue-4 virus within the genome of the YFV 17D strain (YF5.2iv infectious clone) were constructed and characterized for their properties in cell culture and as experimental vaccines in mice. The prM and E proteins appeared to be properly processed and glycosylated, and in plaque reduction neutralization tests and other assays of antigenic specificity, the E proteins exhibited profiles which resembled those of the homologous dengue virus serotypes. Both chimeric viruses replicated in cell lines of vertebrate and mosquito origin to levels comparable to those of homologous dengue viruses but less efficiently than the YF5.2iv parent. YFV/dengue-4 virus, but not YFV/dengue-2 virus, was neurovirulent for 3-week-old mice by intracerebral inoculation; however, both viruses were attenuated when administered by the intraperitoneal route in mice of that age. Single-dose inoculation of either chimeric virus at a dose of 105 PFU by the intraperitoneal route induced detectable levels of neutralizing antibodies against the homologous dengue virus strains. Mice which had been immunized in this manner were fully protected from challenge with homologous neurovirulent dengue viruses by intracerebral inoculation compared to unimmunized mice. Protection was associated with significant increases in geometric mean titers of neutralizing antibody compared to those for unimmunized mice. These data indicate that YFV/dengue virus chimeras elicit antibodies which represent protective memory responses in the mouse model of dengue encephalitis. The levels of neurovirulence and immunogenicity of the chimeric viruses in mice correlate with the degree of adaptation of the dengue virus strain to mice. This study supports ongoing investigations concerning the use of this technology for development of a live attenuated viral vaccine against dengue viruses.

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