Is flavivirus resistance interferon type I-independent?
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Interferon type I comprises a group of major virus-inducible host antiviral factors that control infection with a great number of human and animal viruses. They are ubiquitously expressed cytokines that interfere with virus replication within different cell types by activating a number of host genes and several parallel antiviral pathways. Two major intracellular actors of IFN-I-induced antiviral states are ribonucleic acid-dependent protein kinase and 2'-5'-oligoadenylate synthetases/RNase L, both being induced by IFN-I and activated by viral double stranded ribonucleic acid. In addition, Mx proteins and ribonucleic acid-specific adenosine deaminase have also been implicated in IFN-I-induced antiviral responses to some RNA viruses. Viruses, in turn, have evolved different strategies to escape a control imposed by IFN-I and by IFN-I-induced antiviral factors. The fatal outcome of virus infection as well as the efficiency of IFN-I-based antiviral therapies in its prevention, are determined by complex interactions between viral virulence factors and cellular antiviral IFN-I inducible factors. In the light of these facts and current knowledge on IFN-I involvement in flavivirus infection, I discuss a possible role of IFN-I signalling in resistance to flavivirus infection in a model of congenic mouse strains that express different levels of susceptibility/resistance to common flaviviruses. Specifically, this review emphasizes importance of fully operative 2'-5'-oligoadenylate synthetases/RNase L pathway for the IFN-I-induced stimulation of flavivirus resistance conferred by Flv. (+info)
Flavivirus capsid is a dimeric alpha-helical protein.
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The capsid proteins of two flaviviruses, yellow fever virus and dengue virus, were expressed in Escherichia coli and purified to near homogeneity suitable for biochemical characterization and structure determination by nuclear magnetic resonance. The oligomeric properties of the capsid protein in solution were investigated. In the absence of nucleic acid, both proteins were predominantly dimeric in solution. Further analysis of both proteins with far-UV circular dichroism spectroscopy indicated that they were largely alpha-helical. The secondary structure elements of the dengue virus capsid were determined by chemical shift indexing of the sequence-specific backbone resonance assignments. The dengue virus capsid protein devoid of its C-terminal signal sequence was found to be composed of four alpha helices. The longest alpha helix, 20 residues, is located at the C terminus and has an amphipathic character. In contrast, the N terminus was found to be unstructured and could be removed without disrupting the structural integrity of the protein. (+info)
Structures of immature flavivirus particles.
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Structures of prM-containing dengue and yellow fever virus particles were determined to 16 and 25 A resolution, respectively, by cryoelectron microscopy and image reconstruction techniques. The closely similar structures show 60 icosahedrally organized trimeric spikes on the particle surface. Each spike consists of three prM:E heterodimers, where E is an envelope glycoprotein and prM is the precursor to the membrane protein M. The pre-peptide components of the prM proteins in each spike cover the fusion peptides at the distal ends of the E glycoproteins in a manner similar to the organization of the glycoproteins in the alphavirus spikes. Each heterodimer is associated with an E and a prM transmembrane density. These transmembrane densities represent either an EE or prMprM antiparallel coiled coil by which each protein spans the membrane twice, leaving the C-terminus of each protein on the exterior of the viral membrane, consistent with the predicted membrane-spanning domains of the unprocessed polyprotein. (+info)
Brazilian Flavivirus phylogeny based on NS5.
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In this work, a comprehensive phylogenetic study based on 600 base pair nucleotide and on putative 200 amino acid sequences of NS5 was carried out in order to establish genetic relationships among 15 strains of 10 Brazilian flaviviruses: Bussuquara, Cacipacore, dengue type 1, 2 and 4, Iguape, Ilheus, Rocio, Saint Louis encephalitis (SLE), and yellow fever. Phylogenetic trees were created by neighbor-joining and maximum parsimony methods. These trees showed Brazilian flaviviruses grouped into three main branches: yellow fever branch, dengue branch subdivided in types 1, 2 and 4 branches, and Japanese encephalitis virus (JEV) complex branch including SLE virus strains, Cacipacore, Iguape, Rocio, Ilheus and Bussuquara. Viruses transmitted by Aedes mosquitoes, such as dengue and urban yellow fever, that are also the only Flavivirus causing hemorrhagic fevers in Brazil, were grouped in the same cluster. Encephalitis associated viruses, transmitted by Culex mosquitoes such as JEV complex branch including SLE virus strains, Cacipacore, Iguape, Rocio, Ilheus and Bussuquara were also grouped in the same clade. (+info)
Alteration of clinical outcome and histopathology of yellow fever virus infection in a hamster model by previous infection with heterologous flaviviruses.
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Using a recently described hamster model of severe yellow fever (YF), we examined the hypothesis that prior infection with heterologous flaviviruses protects against severe or fatal YF. Hamsters were singly or sequentially infected with Japanese encephalitis, St. Louis encephalitis, West Nile, and/or dengue-1 viruses, and then challenged with a virulent strain of yellow fever virus (YFV). In contrast to control (naive) hamsters, many of which appeared clinically ill or died after YFV infection, the flavivirus-immune animals remained asymptomatic. The flavivirus-immune hamsters also had a reduced viremia and lower serum levels of alanine aminotransferase and total bilirubin, compared with naive hamsters, following YFV infection. Histologically, livers of animals in the flavivirus-immune and control groups showed comparable levels of multifocal necrapoptosis. However, steatosis was not observed in the flavivirus-immune animals, whereas naive hamsters developed extensive microvesicular steatosis in the liver following YFV infection. These findings suggest that hepatocytic steatosis is an adverse microscopic feature associated with severe disease in YFV infection. Our experimental results support earlier anecdotal reports that prior exposure of humans to heterologous flaviviruses reduces subsequent risk of fatal YFV infection. (+info)
Large genetic differentiation and low variation in vector competence for dengue and yellow fever viruses of Aedes albopictus from Brazil, the United States, and the Cayman Islands.
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We conducted a population genetic analysis of Aedes albopictus collected from 20 sites in Brazil, the United States (Florida, Georgia, and Illinois), and the Cayman Islands. Using isoenzyme analysis, we examined genetic diversity and patterns of gene flow. High genetic differentiation was found among Brazilian samples, and between them and North American samples. Regression analysis of genetic differentiation according to geographic distances indicated that Ae. albopictus samples from Florida were genetically isolated by distance. Infection rates with dengue and yellow fever viruses showed greater differences between two Brazilian samples than between the two North American samples or between a Brazilian sample and a North American sample. Introductions and establishments of new Ae. albopictus populations in the Americas are still in progress, shaping population genetic composition and potentially modifying both dengue and yellow fever transmission patterns. (+info)
Structural basis of a flavivirus recognized by its neutralizing antibody: solution structure of the domain III of the Japanese encephalitis virus envelope protein.
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The flavivirus envelope protein is the dominant antigen in eliciting neutralizing antibodies and plays an important role in inducing immunologic responses in the infected host. We have determined the solution structure of the major antigenic domain (domain III) of the Japanese encephalitis virus (JEV) envelope protein. The JEV domain III forms a beta-barrel type structure composed of six antiparallel beta-strands resembling the immunoglobulin constant domain. We have also identified epitopes of the JEV domain III to its neutralizing antibody by chemical shift perturbation measurements. Site-directed mutagenesis experiments are performed to confirm the NMR results. Our study provides a structural basis for understanding the mechanism of immunologic protection and for rational design of vaccines effective against flaviviruses. (+info)
Immunoassay targeting nonstructural protein 5 to differentiate West Nile virus infection from dengue and St. Louis encephalitis virus infections and from flavivirus vaccination.
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West Nile virus (WNV) is an emerging flavivirus that has caused frequent epidemics since 1996. Besides natural transmission by mosquitoes, WNV can also be transmitted through blood transfusion and organ transplantation, thus heightening the urgency of development of a specific and rapid serologic assay of WNV infection. The current immunoassays lack specificity because they are based on detection of antibodies against WNV structural proteins and immune responses to structural proteins among flaviviruses cross-react to each other. Here, we describe microsphere immunoassays that detect antibodies to nonstructural proteins 3 and 5 (NS3 and NS5). In contrast to immunoassays based on viral envelope and NS3 proteins, the NS5-based assay (i) reliably discriminates between WNV infections and dengue virus or St. Louis encephalitis virus infections, (ii) differentiates between flavivirus vaccination and natural WNV infection, and (iii) indicates recent infections. These unique features of the NS5-based immunoassay will be very useful for both clinical and veterinary diagnosis of WNV infection. (+info)