Journal articles: 'Flaviviru'

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Morita, Eiji, and Youichi Suzuki. "Membrane-Associated Flavivirus Replication Complex—Its Organization and Regulation." Viruses 13, no. 6 (June 3, 2021): 1060. http://dx.doi.org/10.3390/v13061060.

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Flavivirus consists of a large number of arthropod-borne viruses, many of which cause life-threatening diseases in humans. A characteristic feature of flavivirus infection is to induce the rearrangement of intracellular membrane structure in the cytoplasm. This unique membranous structure called replication organelle is considered as a microenvironment that provides factors required for the activity of the flaviviral replication complex. The replication organelle serves as a place to coordinate viral RNA amplification, protein translation, and virion assembly and also to protect the viral replication complex from the cellular immune defense system. In this review, we summarize the current understanding of how the formation and function of membrane-associated flaviviral replication organelle are regulated by cellular factors.

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Fontoura, Marina Alves, Rebeca Fróes Rocha, and Rafael Elias Marques. "Neutrophil Recruitment and Participation in Severe Diseases Caused by Flavivirus Infection." Life 11, no. 7 (July 20, 2021): 717. http://dx.doi.org/10.3390/life11070717.

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Neutrophils are first-line responders to infections and are recruited to target tissues through the action of chemoattractant molecules, such as chemokines. Neutrophils are crucial for the control of bacterial and fungal infections, but their role in the context of viral infections has been understudied. Flaviviruses are important human viral pathogens transmitted by arthropods. Infection with a flavivirus may result in a variety of complex disease manifestations, including hemorrhagic fever, encephalitis or congenital malformations. Our understanding of flaviviral diseases is incomplete, and so is the role of neutrophils in such diseases. Here we present a comprehensive overview on the participation of neutrophils in severe disease forms evolving from flavivirus infection, focusing on the role of chemokines and their receptors as main drivers of neutrophil function. Neutrophil activation during viral infection was shown to interfere in viral replication through effector functions, but the resulting inflammation is significant and may be detrimental to the host. For congenital infections in humans, neutrophil recruitment mediated by CXCL8 would be catastrophic. Evidence suggests that control of neutrophil recruitment to flavivirus-infected tissues may reduce immunopathology in experimental models and patients, with minimal loss to viral clearance. Further investigation on the roles of neutrophils in flaviviral infections may reveal unappreciated functions of this leukocyte population while increasing our understanding of flaviviral disease pathogenesis in its multiple forms.

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Wee, Sheena, Asfa Alli-Shaik, Relus Kek, Hannah L. F. Swa, Wei-Ping Tien, Vanessa W. Lim, Yee-Sin Leo, Lee-Ching Ng, Hapuarachchige C. Hapuarachchi, and Jayantha Gunaratne. "Multiplex targeted mass spectrometry assay for one-shot flavivirus diagnosis." Proceedings of the National Academy of Sciences 116, no. 14 (March 18, 2019): 6754–59. http://dx.doi.org/10.1073/pnas.1817867116.

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Targeted proteomic mass spectrometry is emerging as a salient clinical diagnostic tool to track protein biomarkers. However, its strong analytical properties have not been exploited in the diagnosis and typing of flaviviruses. Here, we report the development of a sensitive and specific single-shot robust assay for flavivirus typing and diagnosis using targeted mass spectrometry technology. Our flavivirus parallel reaction monitoring assay (fvPRM) has the ability to track secreted flaviviral nonstructural protein 1 (NS1) over a broad diagnostic and typing window with high sensitivity, specificity, extendibility, and multiplexing capability. These features, pivotal and pertinent to efficient response toward flavivirus outbreaks, including newly emerging flavivirus strains, circumvent the limitations of current diagnostic assays.fvPRM thus carries high potential in positioning itself as a forerunner in delivering early and accurate diagnosis for disease management.

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van den Elsen, Kaïn, Jun Ping Quek, and Dahai Luo. "Molecular Insights into the Flavivirus Replication Complex." Viruses 13, no. 6 (May 21, 2021): 956. http://dx.doi.org/10.3390/v13060956.

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Flaviviruses are vector-borne RNA viruses, many of which are clinically relevant human viral pathogens, such as dengue, Zika, Japanese encephalitis, West Nile and yellow fever viruses. Millions of people are infected with these viruses around the world each year. Vaccines are only available for some members of this large virus family, and there are no effective antiviral drugs to treat flavivirus infections. The unmet need for vaccines and therapies against these flaviviral infections drives research towards a better understanding of the epidemiology, biology and immunology of flaviviruses. In this review, we discuss the basic biology of the flavivirus replication process and focus on the molecular aspects of viral genome replication. Within the virus-induced intracellular membranous compartments, flaviviral RNA genome replication takes place, starting from viral poly protein expression and processing to the assembly of the virus RNA replication complex, followed by the delivery of the progeny viral RNA to the viral particle assembly sites. We attempt to update the latest understanding of the key molecular events during this process and highlight knowledge gaps for future studies.

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Thibodeaux, Brett A., and John T. Roehrig. "Development of a Human-Murine Chimeric Immunoglobulin M Antibody for Use in the Serological Detection of Human Flavivirus Antibodies." Clinical and Vaccine Immunology 16, no. 5 (March 18, 2009): 679–85. http://dx.doi.org/10.1128/cvi.00354-08.

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ABSTRACT Current diagnosis of human flaviviral infections relies heavily on serological techniques such as the immunoglobulin M (IgM) antibody capture enzyme-linked immunosorbent assay (MAC-ELISA). Broad application of this assay is hindered by a lack of standardized human positive-control sera that react with the wide variety of flaviviruses that can cause human disease, e.g., dengue virus (DENV), West Nile virus (WNV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and St. Louis encephalitis virus (SLEV). We have created a human-murine chimeric antibody combining the variable regions of the broadly flavivirus cross-reactive murine monoclonal antibody (MAb) 6B6C-1 and the constant region of human IgM to produce a standardized reagent capable of replacing human positive-control sera in a MAC-ELISA for the diagnosis of all human flaviviral infections. The human-murine chimeric IgM antibody secreted from plasmid-transformed Sp2/0-Ag14 cells had a level of serological activity identical to that of 6B6C-1 as measured by ELISA, immunoblotting, and MAC-ELISA for multiple members of the flavivirus genus, including WNV, SLEV, YFV, DENV, and JEV.

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Seo, Min-Goo, Hak Seon Lee, Sung-Chan Yang, Byung-Eon Noh, Tae-Kyu Kim, Wook-Gyo Lee, and Hee Il Lee. "National Monitoring of Mosquito Populations and Molecular Analysis of Flavivirus in the Republic of Korea in 2020." Microorganisms 9, no. 10 (October 2, 2021): 2085. http://dx.doi.org/10.3390/microorganisms9102085.

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The Korea Disease Control and Prevention Agency has established centers at 16 locations to screen vector populations and pathogens. The aims of this study were to determine the relative spatiotemporal distributions of mosquitoes that are flavivirus vectors, and to correlate them with instances of flaviviral disease in the Republic of Korea (ROK). We collected 67,203 mosquitoes in traps at 36 collection sites in 30 urban regions and migratory bird habitats in 2020. The trap index was 36.6, and the predominant mosquito species were the Culex pipiens complex, Armigeres subalbatus, Aedes albopictus, Aedes vexans, and Culex tritaeniorhynchus. The mosquitoes were pooled into 4953 pools to monitor flavivirus infection. We determined that the minimum infection rate of flavivirus was 0.01%. Japanese encephalitis virus (JEV) was detected in only seven pools of Culex orientalis from Sangju, and we isolated JVE from two pools. All detected JEV was found to be genotype V by phylogenetic analysis. To the best of our knowledge, this is the first study to isolate genotype V JVE from Culex orientalis in the ROK. Subsequent geographical and ecological studies on mosquitoes will help improve our understanding of the relative risk of flavivirus infection. Future studies should analyze mosquito species distribution and improve flavivirus monitoring and long-term surveillance.

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Qiu, Yang, Yan-Peng Xu, Miao Wang, Meng Miao, Hui Zhou, Jiuyue Xu, Jing Kong, et al. "Flavivirus induces and antagonizes antiviral RNA interference in both mammals and mosquitoes." Science Advances 6, no. 6 (February 2020): eaax7989. http://dx.doi.org/10.1126/sciadv.aax7989.

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Mosquito-borne flaviviruses infect both mammals and mosquitoes. RNA interference (RNAi) has been demonstrated as an anti-flavivirus mechanism in mosquitoes; however, whether and how flaviviruses induce and antagonize RNAi-mediated antiviral immunity in mammals remains unknown. We show that the nonstructural protein NS2A of dengue virus-2 (DENV2) act as a viral suppressor of RNAi (VSR). When NS2A-mediated RNAi suppression was disabled, the resulting mutant DENV2 induced Dicer-dependent production of abundant DENV2-derived siRNAs in differentiated mammalian cells. VSR-disabled DENV2 showed severe replication defects in mosquito and mammalian cells and in mice that were rescued by RNAi deficiency. Moreover, NS2As of multiple flaviviruses act as VSRs in vitro and during viral infection in both organisms. Overall, our findings demonstrate that antiviral RNAi can be induced by flavivirus, while flavivirus uses NS2A as a bona fide VSR to evade RNAi in mammals and mosquitoes, highlighting the importance of RNAi in flaviviral vector-host life cycles.

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Wu, Bingan, Zhongtian Qi, and Xijing Qian. "Recent Advancements in Mosquito-Borne Flavivirus Vaccine Development." Viruses 15, no. 4 (March 23, 2023): 813. http://dx.doi.org/10.3390/v15040813.

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Lately, the global incidence of flavivirus infection has been increasing dramatically and presents formidable challenges for public health systems around the world. Most clinically significant flaviviruses are mosquito-borne, such as the four serotypes of dengue virus, Zika virus, West Nile virus, Japanese encephalitis virus and yellow fever virus. Until now, no effective antiflaviviral drugs are available to fight flaviviral infection; thus, a highly immunogenic vaccine would be the most effective weapon to control the diseases. In recent years, flavivirus vaccine research has made major breakthroughs with several vaccine candidates showing encouraging results in preclinical and clinical trials. This review summarizes the current advancement, safety, efficacy, advantages and disadvantages of vaccines against mosquito-borne flaviviruses posing significant threats to human health.

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Bidet, Katell, and Mariano A. Garcia-Blanco. "Flaviviral RNAs: weapons and targets in the war between virus and host." Biochemical Journal 462, no. 2 (August 7, 2014): 215–30. http://dx.doi.org/10.1042/bj20140456.

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Flaviviruses are a genus of (+)ssRNA (positive ssRNA) enveloped viruses that replicate in the cytoplasm of cells of diverse species from arthropods to mammals. Many are important human pathogens such as DENV-1–4 (dengue virus types 1–4), WNV (West Nile virus), YFV (yellow fever virus), JEV (Japanese encephalitis virus) and TBEV (tick-borne encephalitis). Given their RNA genomes it is not surprising that flaviviral life cycles revolve around critical RNA transactions. It is these we highlight in the present article. First, we summarize the mechanisms governing flaviviral replication and the central role of conserved RNA elements and viral protein–RNA interactions in RNA synthesis, translation and packaging. Secondly, we focus on how host RNA-binding proteins both benefit and inhibit flaviviral replication at different stages of their life cycle in mammalian hosts. Thirdly, we cover recent studies on viral non-coding RNAs produced in flavivirus-infected cells and how these RNAs affect various aspects of cellular RNA metabolism. Together, the article puts into perspective the central role of flaviviral RNAs in modulating both viral and cellular functions.

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Blahove, Maria Raisa, and James Richard Carter. "Flavivirus Persistence in Wildlife Populations." Viruses 13, no. 10 (October 18, 2021): 2099. http://dx.doi.org/10.3390/v13102099.

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A substantial number of humans are at risk for infection by vector-borne flaviviruses, resulting in considerable morbidity and mortality worldwide. These viruses also infect wildlife at a considerable rate, persistently cycling between ticks/mosquitoes and small mammals and reptiles and non-human primates and humans. Substantially increasing evidence of viral persistence in wildlife continues to be reported. In addition to in humans, viral persistence has been shown to establish in mammalian, reptile, arachnid, and mosquito systems, as well as insect cell lines. Although a considerable amount of research has centered on the potential roles of defective virus particles, autophagy and/or apoptosis-induced evasion of the immune response, and the precise mechanism of these features in flavivirus persistence have yet to be elucidated. In this review, we present findings that aid in understanding how vector-borne flavivirus persistence is established in wildlife. Research studies to be discussed include determining the critical roles universal flavivirus non-structural proteins played in flaviviral persistence, the advancement of animal models of viral persistence, and studying host factors that allow vector-borne flavivirus replication without destructive effects on infected cells. These findings underscore the viral–host relationships in wildlife animals and could be used to elucidate the underlying mechanisms responsible for the establishment of viral persistence in these animals.

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11

Geiss, Brian J., Hillary J. Stahla-Beek, Amanda M. Hannah, Hamid H. Gari, Brittney R. Henderson, Bejan J. Saeedi, and Susan M. Keenan. "A High-Throughput Screening Assay for the Identification of Flavivirus NS5 Capping Enzyme GTP-Binding Inhibitors." Journal of Biomolecular Screening 16, no. 8 (July 25, 2011): 852–61. http://dx.doi.org/10.1177/1087057111412183.

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There are no effective antivirals currently available for the treatment of flavivirus infection in humans. As such, the identification and characterization of novel drug target sites are critical to developing new classes of antiviral drugs. The flavivirus NS5 N-terminal capping enzyme (CE) is vital for the formation of the viral RNA cap structure, which directs viral polyprotein translation and stabilizes the 5′ end of the viral genome. The structure of the flavivirus CE has been solved, and a detailed understanding of the CE–guanosine triphosphate (GTP) and CE–RNA cap interactions is available. Because of the essential nature of the interaction for viral replication, disrupting CE–GTP binding is an attractive approach for drug development. The authors have previously developed a robust assay for monitoring CE–GTP binding in real time. They adapted this assay for high-throughput screening and performed a pilot screen of 46 323 commercially available compounds. A number of small-molecule inhibitors capable of displacing a fluorescently labeled GTP in vitro were identified, and a second functional assay was developed to identify false positives. The results presented indicate that the flavivirus CE cap-binding site is a valuable new target site for antiviral drug discovery and should be further exploited for broad-spectrum anti-flaviviral drug development.

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12

Modhiran, Naphak, Hao Song, Lidong Liu, Cheryl Bletchly, Lou Brillault, Alberto A. Amarilla, Xiaoying Xu, et al. "A broadly protective antibody that targets the flavivirus NS1 protein." Science 371, no. 6525 (January 7, 2021): 190–94. http://dx.doi.org/10.1126/science.abb9425.

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There are no approved flaviviral therapies and the development of vaccines against flaviruses has the potential of being undermined by antibody-dependent enhancement (ADE). The flavivirus nonstructural protein 1 (NS1) is a promising vaccine antigen with low ADE risk but has yet to be explored as a broad-spectrum therapeutic antibody target. Here, we provide the structural basis of NS1 antibody cross-reactivity through cocrystallization of the antibody 1G5.3 with NS1 proteins from dengue and Zika viruses. The 1G5.3 antibody blocks multi-flavivirus NS1-mediated cell permeability in disease-relevant cell lines, and therapeutic application of 1G5.3 reduces viremia and improves survival in dengue, Zika, and West Nile virus murine models. Finally, we demonstrate that 1G5.3 protection is independent of effector function, identifying the 1G5.3 epitope as a key site for broad-spectrum antiviral development.

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Lee, Chyan-Jang, Hui-Ru Lin, Ching-Len Liao, and Yi-Ling Lin. "Cholesterol Effectively Blocks Entry of Flavivirus." Journal of Virology 82, no. 13 (April 30, 2008): 6470–80. http://dx.doi.org/10.1128/jvi.00117-08.

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ABSTRACT Japanese encephalitis virus (JEV) and dengue virus serotype 2 (DEN-2) are enveloped flaviviruses that enter cells through receptor-mediated endocytosis and low pH-triggered membrane fusion and then replicate in intracellular membrane structures. Lipid rafts, cholesterol-enriched lipid-ordered membrane domains, are platforms for a variety of cellular functions. In this study, we found that disruption of lipid raft formation by cholesterol depletion with methyl-β-cyclodextrin or cholesterol chelation with filipin III reduces JEV and DEN-2 infection, mainly at the intracellular replication steps and, to a lesser extent, at viral entry. Using a membrane flotation assay, we found that several flaviviral nonstructural proteins are associated with detergent-resistant membrane structures, indicating that the replication complex of JEV and DEN-2 localizes to the membranes that possess the lipid raft property. Interestingly, we also found that addition of cholesterol readily blocks flaviviral infection, a result that contrasts with previous reports of other viruses, such as Sindbis virus, whose infectivity is enhanced by cholesterol. Cholesterol mainly affected the early step of the flavivirus life cycle, because the presence of cholesterol during viral adsorption greatly blocked JEV and DEN-2 infectivity. Flavirial entry, probably at fusion and RNA uncoating steps, was hindered by cholesterol. Our results thus suggest a stringent requirement for membrane components, especially with respect to the amount of cholesterol, in various steps of the flavivirus life cycle.

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Errico, John M., Laura A. VanBlargan, Christopher A. Nelson, Michael S. Diamond, and Daved H. Fremont. "Structural and Antigenic Features of Powassan Virus Envelope Protein." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 126.27. http://dx.doi.org/10.4049/jimmunol.200.supp.126.27.

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Abstract Flaviviruses, such as West-Nile virus and Dengue virus, are insect-transmitted positive-sense RNA viruses that cause substantial morbidity and mortality worldwide. Powassan virus is an emerging encephalitic tick-borne flavivirus endemic to the northern United States, and is currently the only tick-transmitted flavivirus known to infect humans in North America. In cases of severe neurological disease, up to 10% of patients die of Powassan encephalitis, while many survivors are left with long-term neurological sequelae. Despite this, no vaccines or therapeutics are currently available to treat Powassan virus infection. Flaviviral vaccination efforts are commonly foiled by an inability to generate potent neutralizing responses, and by genesis of cross-reactive antibodies that paradoxically enhance infection by heterologous flaviviruses. These neutralizing antibodies, and their cross-reactive counterparts, commonly target structurally homologous epitopes present on many flaviviruses. Thus, understanding these epitopes has important implications for vaccine design. Little is known about the structure of Powassan virus envelope protein or host antibodies that target it. We have recombinantly expressed Powassan virus envelope protein and are currently working to determine its structure. As well, a panel of Powassan-virus specific monoclonal antibodies has been developed. Utilizing our recombinant protein, we are characterizing the epitopes these antibodies utilize as well as their biochemical and functional properties. These findings will aid vaccine and therapeutic design for Powassan virus and expand our understanding of the quintessential antigenic and structural features of flaviviral envelope proteins.

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Sanford, Thomas J., Harriet V. Mears, Teodoro Fajardo, Nicolas Locker, and Trevor R. Sweeney. "Circularization of flavivirus genomic RNA inhibits de novo translation initiation." Nucleic Acids Research 47, no. 18 (August 8, 2019): 9789–802. http://dx.doi.org/10.1093/nar/gkz686.

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Abstract Members of the Flaviviridae family, including dengue virus (DENV) and yellow fever virus, cause serious disease in humans, whilst maternal infection with Zika virus (ZIKV) can induce microcephaly in newborns. Following infection, flaviviral RNA genomes are translated to produce the viral replication machinery but must then serve as a template for the transcription of new genomes. However, the ribosome and viral polymerase proceed in opposite directions along the RNA, risking collisions and abortive replication. Whilst generally linear, flavivirus genomes can adopt a circular conformation facilitated by long-range RNA–RNA interactions, shown to be essential for replication. Using an in vitro reconstitution approach, we demonstrate that circularization inhibits de novo translation initiation on ZIKV and DENV RNA, whilst the linear conformation is translation-competent. Our results provide a mechanism to clear the viral RNA of ribosomes in order to promote efficient replication and, therefore, define opposing roles for linear and circular conformations of the flavivirus genome.

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Neufeldt, Christopher J., Mirko Cortese, Pietro Scaturro, Berati Cerikan, Jeremy Wideman, Keisuke Tabata, Thais Morase, Olga Oleksiuk, Andreas Pichlmair, and Ralf Bartenschlager. "ER-Shaping Atlastin Proteins Act as Central Hubs to Promote Flavivirus Replication and Virion Assembly." Proceedings 50, no. 1 (June 10, 2020): 31. http://dx.doi.org/10.3390/proceedings2020050031.

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Members of the Flavivirus genus rely extensively on the host cell endomembrane network to generate complex membranous replication organelles (ROs) that facilitate viral genome replication and the production of virus particles. For dengue virus and Zika virus, these ROs included vesicles which are formed through membrane invagination into the endoplasmic reticulum (ER) lumen, termed invaginated vesicles or vesicle packets (VPs), as well as large areas of bundled smooth ER, termed convoluted membranes. Though the morphology of these virus-induced membrane structures has been well characterized, the viral and host constituents that make up flaviviral ROs are still poorly understood. Here, we identified a subset of ER resident proteins (atlastins), normally required for maintaining ER tubule networks, as critical host factors for flavivirus infection. Specific changes in atlastin (ATL) levels had dichotomous effects on flaviviruses with ATL2 depletion, leading to replication organelle defects and ATL3 depletion to changes in viral assembly/release pathways. These different depletion phenotypes allowed us to exploit virus infection to characterize non-conserved functional domains between the three atlastin paralogues. Additionally, we established the ATL interactome and show how it is reprogrammed upon viral infection. Screening of specific ATL interactors confirmed non-redundant ATL functions and identified a role for ATL3 in vesicle trafficking. Our data demonstrate that ATLs are central host factors that coordinate the ER network and shape the ER during flavivirus infection.

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Uchil, Pradeep Devappa, Anil V. A. Kumar, and Vijaya Satchidanandam. "Nuclear Localization of Flavivirus RNA Synthesis in Infected Cells." Journal of Virology 80, no. 11 (June 1, 2006): 5451–64. http://dx.doi.org/10.1128/jvi.01982-05.

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ABSTRACT Flaviviral replication is believed to be exclusively cytoplasmic, occurring within virus-induced membrane-bound replication complexes in the host cytoplasm. Here we show that a significant proportion (20%) of the total RNA-dependent RNA polymerase (RdRp) activity from cells infected with West Nile virus, Japanese encephalitis virus (JEV), and dengue virus is resident within the nucleus. Consistent with this, the major replicase proteins NS3 and NS5 of JEV also localized within the nucleus. NS5 was found distributed throughout the nucleoplasm, but NS3 was present at sites of active flaviviral RNA synthesis, colocalizing with NS5, and visible as distinct foci along the inner periphery of the nucleus by confocal and immunoelectron microscopy. Both these viral replicase proteins were also present in the nuclear matrix, colocalizing with the peripheral lamina, and revealed a well-entrenched nuclear location for the viral replication complex. In keeping with this observation, antibodies to either NS3 or NS5 coimmunoprecipitated the other protein from isolated nuclei along with newly synthesized viral RNA. Taken together these data suggest an absolute requirement for both of the replicase proteins for nucleus-localized synthesis of flavivirus RNA. Thus, we conclusively demonstrate for the first time that the host cell nucleus functions as an additional site for the presence of functionally active flaviviral replicase complex.

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Habarugira, Gervais, Jasmin Moran, Jessica J. Harrison, Sally R. Isberg, Jody Hobson-Peters, Roy A. Hall, and Helle Bielefeldt-Ohmann. "Evidence of Infection with Zoonotic Mosquito-Borne Flaviviruses in Saltwater Crocodiles (Crocodylus porosus) in Northern Australia." Viruses 14, no. 5 (May 21, 2022): 1106. http://dx.doi.org/10.3390/v14051106.

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The risk of flavivirus infections among the crocodilian species was not recognised until West Nile virus (WNV) was introduced into the Americas. The first outbreaks caused death and substantial economic losses in the alligator farming industry. Several other WNV disease episodes have been reported in crocodilians in other parts of the world, including Australia and Africa. Considering that WNV shares vectors with other flaviviruses, crocodilians are highly likely to also be exposed to flaviviruses other than WNV. A serological survey for flaviviral infections was conducted on saltwater crocodiles (Crocodylus porosus) at farms in the Northern Territory, Australia. Five hundred serum samples, collected from three crocodile farms, were screened using a pan-flavivirus-specific blocking ELISA. The screening revealed that 26% (n = 130/500) of the animals had antibodies to flaviviruses. Of these, 31.5% had neutralising antibodies to WNVKUN (Kunjin strain), while 1.5% had neutralising antibodies to another important flavivirus pathogen, Murray Valley encephalitis virus (MVEV). Of the other flaviviruses tested for, Fitzroy River virus (FRV) was the most frequent (58.5%) in which virus neutralising antibodies were detected. Our data indicate that farmed crocodiles in the Northern Territory are exposed to a range of potentially zoonotic flaviviruses, in addition to WNVKUN. While these flaviviruses do not cause any known diseases in crocodiles, there is a need to investigate whether infected saltwater crocodiles can develop a viremia to sustain the transmission cycle or farmed crocodilians can be used as sentinels to monitor the dynamics of arboviral infections in tropical areas.

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Cook, Shelley, Shannon N. Bennett, Edward C. Holmes, Reine De Chesse, Gregory Moureau, and Xavier de Lamballerie. "Isolation of a new strain of the flavivirus cell fusing agent virus in a natural mosquito population from Puerto Rico." Journal of General Virology 87, no. 4 (April 1, 2006): 735–48. http://dx.doi.org/10.1099/vir.0.81475-0.

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The genus Flavivirus contains approximately 70 single-stranded, positive-sense RNA viruses that are mosquito-borne, tick-borne or have no known vector. Two discoveries support previous suggestions of the existence of a large number of unsampled flaviviruses: (i) a new flavivirus, Kamiti River virus, was recently isolated from Kenyan mosquitoes, and (ii) sequences with high similarity to those of flaviviruses have been found integrated into the genome of Aedes mosquitoes, suggesting a past infection with a virus (or viruses) that has yet to be discovered. These sequences were related most closely to a flavivirus that infects insects alone, cell fusing agent virus (CFAV). CFAV was originally isolated in the laboratory from an Aedes aegypti cell line. To date, this virus had not been found in the wild. In the present study, over 40 isolates of a novel strain of CFAV were discovered from mature mosquitoes sampled from the wild in Puerto Rico. The viral strain was present in a range of mosquito species, including Aedes aegypti, Aedes albopictus and Culex sp., from numerous locations across the island and, importantly, in mosquitoes of both sexes, suggesting vertical transmission. Here, results from viral screening, and cell culture and molecular identification of the infected mosquitoes are presented. Experimental-infection tests were also conducted by using the original CFAV strain and a highly efficient reverse-transcription mechanism has been documented, in which initiation of copying occurs at the 3′ terminus of either the genomic RNA or the intermediate of replication, potentially elucidating the mechanism by which flaviviral sequences may have integrated into mosquito genomes.

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Nelson, Corey, Tyler Mrozowich, Darren L. Gemmill, Sean M. Park, and Trushar R. Patel. "Human DDX3X Unwinds Japanese Encephalitis and Zika Viral 5′ Terminal Regions." International Journal of Molecular Sciences 22, no. 1 (January 2, 2021): 413. http://dx.doi.org/10.3390/ijms22010413.

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Flavivirus genus includes many deadly viruses such as the Japanese encephalitis virus (JEV) and Zika virus (ZIKV). The 5′ terminal regions (TR) of flaviviruses interact with human proteins and such interactions are critical for viral replication. One of the human proteins identified to interact with the 5′ TR of JEV is the DEAD-box helicase, DDX3X. In this study, we in vitro transcribed the 5′ TR of JEV and demonstrated its direct interaction with recombinant DDX3X (Kd of 1.66 ± 0.21 µM) using microscale thermophoresis (MST). Due to the proposed structural similarities of 5′ and 3′ TRs of flaviviruses, we investigated if the ZIKV 5′ TR could also interact with human DDX3X. Our MST studies suggested that DDX3X recognizes ZIKV 5′ TR with a Kd of 7.05 ± 0.75 µM. Next, we performed helicase assays that suggested that the binding of DDX3X leads to the unwinding of JEV and ZIKV 5′ TRs. Overall, our data indicate, for the first time, that DDX3X can directly bind and unwind in vitro transcribed flaviviral TRs. In summary, our work indicates that DDX3X could be further explored as a therapeutic target to inhibit Flaviviral replication

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Yu, Chia-Yi, Yun-Wei Hsu, Ching-Len Liao, and Yi-Ling Lin. "Flavivirus Infection Activates the XBP1 Pathway of the Unfolded Protein Response To Cope with Endoplasmic Reticulum Stress." Journal of Virology 80, no. 23 (September 20, 2006): 11868–80. http://dx.doi.org/10.1128/jvi.00879-06.

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ABSTRACT The unfolded protein response (UPR) is a coordinated change in gene expression triggered by perturbations in functions of the endoplasmic reticulum (ER). XBP1, a key transcription factor of the UPR, is activated by an IRE1-mediated splicing event, which results in a frameshift and encodes a protein with transcriptional activity. Here, we report that XBP1 was activated during flaviviral infection, as evidenced by XBP1 mRNA splicing and protein expression, as well as induction of the downstream genes ERdj4, EDEM1, and p58(IPK) in Japanese encephalitis virus (JEV)- and dengue virus serotype 2 (DEN-2)-infected cells. Reporter systems based on IRE1-mediated XBP1 splicing were established, and several flaviviral proteins associated with the ER, including glycoproteins and small hydrophobic membrane-anchored proteins, were found to trigger the splicing event. Notably, nonstructural protein NS2B-3 of DEN-2, but not of JEV, was a potent inducer of XBP1 splicing through an unclear mechanism(s). Reduction of XBP1 by a small interfering RNA had no effect on cells' susceptibility to the two viruses but exacerbated the flavivirus-induced cytopathic effects. Overall, flaviviruses trigger the XBP1 signaling pathway and take advantage of this cellular response to alleviate virus-induced cytotoxicity.

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Sotcheff, Stephanea, and Andrew Routh. "Understanding Flavivirus Capsid Protein Functions: The Tip of the Iceberg." Pathogens 9, no. 1 (January 5, 2020): 42. http://dx.doi.org/10.3390/pathogens9010042.

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Flaviviruses are enveloped positive-sense single-stranded RNA arboviruses, infectious to humans and many other animals and are transmitted primarily via tick or mosquito vectors. Capsid is the primary structural protein to interact with viral genome within virus particles and is therefore necessary for efficient packaging. However, in cells, capsid interacts with many proteins and nucleic acids and we are only beginning to understand the broad range of functions of flaviviral capsids. It is known that capsid dimers interact with the membrane of lipid droplets, aiding in both viral packaging and storage of capsid prior to packaging. However, capsid dimers can bind a range of nucleic acid templates in vitro, and likely interact with a range of targets during the flavivirus lifecycle. Capsid may interact with host RNAs, resulting in altered RNA splicing and RNA transcription. Capsid may also bind short interfering-RNAs and has been proposed to sequester these species to protect flaviviruses from the invertebrate siRNA pathways. Capsid can also be found in the nucleolus, where it wreaks havoc on ribosome biogenesis. Here we review flavivirus capsid structure, nucleic acid interactions and how these give rise to multiple functions. We also discuss how these features might be exploited either in the design of effective antivirals or novel vaccine strategies.

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Chuang, Fu-Kai, Ching-Len Liao, Ming-Kuan Hu, Yi-Lin Chiu, An-Rong Lee, Shih-Ming Huang, Yu-Lung Chiu, et al. "Antiviral Activity of Compound L3 against Dengue and Zika Viruses In Vitro and In Vivo." International Journal of Molecular Sciences 21, no. 11 (June 5, 2020): 4050. http://dx.doi.org/10.3390/ijms21114050.

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Dengue virus (DENV) and Zika virus (ZIKV) are mosquito-borne flaviviruses that cause severe illness after infection. Currently, there are no specific or effective treatments against DENV and ZIKV. Previous studies have shown that tyrosine kinase activities and signal transduction are involved in flavivirus replication, suggesting a potential therapeutic strategy for DENV and ZIKV. In this study, we found that compound L3 can significantly reduce viral protein expression and viral titers in HEK-293, MCF-7, HepG2, and Huh-7 cells and exhibits superior therapeutic efficacy against flaviviral infection compared to other tyrosine kinase inhibitors. In addition, compound L3 can decrease endogenous HER2 activation and inhibit the phosphorylation of the HER2 downstream signaling molecules Src and ERK1/2, the levels of which have been associated with viral protein expression in MCF-7 cells. Moreover, silencing HER2 diminished DENV-2 and ZIKV expression in MCF-7 cells, which suggests that HER2 activity is involved in flavivirus replication. Furthermore, in DENV-2-infected AG129 mice, treatment with compound L3 increased the survival rates and reduced the viremia levels. Overall, compound L3 demonstrates therapeutic efficacy both in vitro and in vivo and could be developed as a promising antiviral drug against emerging flaviviruses or for concurrent DENV and ZIKV outbreaks.

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Ngono, Annie Elong, Thasneem Syed, Anh-Viet Nguyen, Jose Regla Nava, Mercylia Susantono, Darina Spasova, Allison Aguilar, et al. "CD8+ T cells mediate an NS3-based vaccine protection against Zika virus." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 95.4. http://dx.doi.org/10.4049/jimmunol.204.supp.95.4.

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Abstract Zika virus (ZIKV), a member of the flaviviridae family, is associated with severe congenital malformations in infants born to infected mothers, and with neurological disorders, such as Guillain–Barré syndrome, in infected adults. To date, the development of anti-flavivirus vaccines has focused predominantly on the induction of neutralizing antibodies. Paradoxically, a suboptimal antibody response may enhance disease severity upon subsequent flaviviral infection through a phenomenon known as antibody-dependent enhancement. Thus, alternative approaches to ZIKV vaccine design are necessary. Here, we report induction of a protective anti-ZIKV CD8+ T cell response in the HLA-B*0702 Ifnar1−/− transgenic mouse model using an alphavirus-based replicon RNA vaccine expressing ZIKV nonstructural protein NS3, a potent T cell antigen. The NS3 vaccine did not induce an antibody response, but elicited polyfunctional CD8+ T cells that were necessary and sufficient for controlling viral burden and preventing death in lethally infected adult mice. In addition, the NS3 vaccine prevented fetal growth restriction and death in infected pregnant mice. These data identify CD8+ T cells as the major mediators of the ZIKV NS3 vaccine-induced protection and suggest a new strategy to develop safe and effective anti-flavivirus vaccines that avoid inadvertent antibody-dependent enhancement.

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TEZCAN, Seda, Serpil KIZILDAMAR, Mahmut ÜLGER, Gönül ASLAN, Naci TİFTİK, Aykut ÖZKUL, Gürol EMEKDAŞ, Matthias NIEDRIG, and Koray ERGÜNAY. "Flavivirus Seroepidemiology in Blood Donors in Mersin Province, Turkey." Mikrobiyoloji Bulteni 48, no. 4 (October 28, 2014): 606–17. http://dx.doi.org/10.5578/mb.8301.

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Delfin-Riela, Triana, Martín Rossotti, Romina Alvez-Rosado, Carmen Leizagoyen, and Gualberto González-Sapienza. "Highly Sensitive Detection of Zika Virus Nonstructural Protein 1 in Serum Samples by a Two-Site Nanobody ELISA." Biomolecules 10, no. 12 (December 9, 2020): 1652. http://dx.doi.org/10.3390/biom10121652.

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The Zika virus was introduced in Brazil in 2015 and, shortly after, spread all over the Americas. Nowadays, it remains present in more than 80 countries and represents a major threat due to some singularities among other flaviviruses. Due to its easy transmission, high percentage of silent cases, the severity of its associated complications, and the lack of prophylactic methods and effective treatments, it is essential to develop reliable and rapid diagnostic tests for early containment of the infection. Nonstructural protein 1 (NS1), a glycoprotein involved in all flavivirus infections, is secreted since the beginning of the infection into the blood stream and has proven to be a valuable biomarker for the early diagnosis of other flaviviral infections. Here, we describe the development of a highly sensitive nanobody ELISA for the detection of the NS1 protein in serum samples. Nanobodies were selected from a library generated from a llama immunized with Zika NS1 (ZVNS1) by a two-step high-throughput screening geared to identify the most sensitive and specific nanobody pairs. The assay was performed with a sub-ng/mL detection limit in the sera and showed excellent reproducibility and accuracy when validated with serum samples spiked with 0.80, 1.60, or 3.10 ng/mL of ZVNS1. Furthermore, the specificity of the developed ELISA was demonstrated using a panel of flavivirus’ NS1 proteins; this is of extreme relevance in countries endemic for more than one flavivirus. Considering that the nanobody sequences are provided, the assay can be reproduced in any laboratory at low cost, which may help to strengthen the diagnostic capacity of the disease even in low-resource countries.

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Choi, Kyung H. "The Role of the Stem-Loop A RNA Promoter in Flavivirus Replication." Viruses 13, no. 6 (June 9, 2021): 1107. http://dx.doi.org/10.3390/v13061107.

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An essential challenge in the lifecycle of RNA viruses is identifying and replicating the viral genome amongst all the RNAs present in the host cell cytoplasm. Yet, how the viral polymerase selectively recognizes and copies the viral RNA genome is poorly understood. In flaviviruses, the 5′-end of the viral RNA genome contains a 70 nucleotide-long stem-loop, called stem-loop A (SLA), which functions as a promoter for genome replication. During replication, flaviviral polymerase NS5 specifically recognizes SLA to both initiate viral RNA synthesis and to methylate the 5′ guanine cap of the nascent RNA. While the sequences of this region vary between different flaviviruses, the three-way junction arrangement of secondary structures is conserved in SLA, suggesting that viruses recognize a common structural feature to replicate the viral genome rather than a particular sequence. To better understand the molecular basis of genome recognition by flaviviruses, we recently determined the crystal structures of flavivirus SLAs from dengue virus (DENV) and Zika virus (ZIKV). In this review, I will provide an overview of (1) flaviviral genome replication; (2) structures of viral SLA promoters and NS5 polymerases; and (3) and describe our current model of how NS5 polymerases specifically recognize the SLA at the 5′ terminus of the viral genome to initiate RNA synthesis at the 3′ terminus.

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Wu, Shu-Fen, Chyan-Jang Lee, Ching-Len Liao, Raymond A. Dwek, Nicole Zitzmann, and Yi-Ling Lin. "Antiviral Effects of an Iminosugar Derivative on Flavivirus Infections." Journal of Virology 76, no. 8 (April 15, 2002): 3596–604. http://dx.doi.org/10.1128/jvi.76.8.3596-3604.2002.

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ABSTRACT Endoplasmic reticulum (ER) α-glucosidase inhibitors, which block the trimming step of N-linked glycosylation, have been shown to eliminate the production of several ER-budding viruses. Here we investigated the effects of one such inhibitor, N-nonyl-deoxynojirimycin (NN-DNJ), a 9-carbon alkyl iminosugar derivative, on infection by Japanese encephalitis virus (JEV) and dengue virus serotype 2 (DEN-2). In the presence of NN-DNJ, JEV and DEN-2 infections were suppressed in a dose-dependent manner. This inhibitory effect appeared to influence DEN-2 infection more than JEV infection, since lower concentrations of NN-DNJ substantially blocked DEN-2 replication. Secretion of the flaviviral glycoproteins E and NS1 was greatly reduced, and levels of DEN-2 viral RNA replication measured by fluorogenic reverse transcription-PCR were also decreased, by NN-DNJ. Notably, the viral glycoproteins, prM, E, and NS1 were found to associate transiently with the ER chaperone calnexin, and this interaction was affected by NN-DNJ, suggesting a potential role of calnexin in the folding of flaviviral glycoproteins. Additionally, in a mouse model of lethal challenge by JEV infection, oral delivery of NN-DNJ reduced the mortality rate. These findings show that NN-DNJ has an antiviral effect on flavivirus infection, likely through interference with virus replication at the posttranslational modification level, occurring mainly in the ER.

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Álvarez-Fernández, Hadrián, Patricia Mingo-Casas, Ana-Belén Blázquez, Flavia Caridi, Juan Carlos Saiz, María-Jesús Pérez-Pérez, Miguel A. Martín-Acebes, and Eva-María Priego. "Allosteric Inhibition of Neutral Sphingomyelinase 2 (nSMase2) by DPTIP: From Antiflaviviral Activity to Deciphering Its Binding Site through In Silico Studies and Experimental Validation." International Journal of Molecular Sciences 23, no. 22 (November 11, 2022): 13935. http://dx.doi.org/10.3390/ijms232213935.

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Flavivirus comprises globally emerging and re-emerging pathogens such as Zika virus (ZIKV), Dengue virus (DENV), and West Nile virus (WNV), among others. Although some vaccines are available, there is an unmet medical need as no effective antiviral treatment has been approved for flaviviral infections. The development of host-directed antivirals (HDAs) targeting host factors that are essential for viral replication cycle offers the opportunity for the development of broad-spectrum antivirals. In the case of flaviviruses, recent studies have revealed that neutral sphingomyelinase 2, (nSMase2), involved in lipid metabolism, plays a key role in WNV and ZIKV infection. As a proof of concept, we have determined the antiviral activity of the non-competitive nSMase2 inhibitor DPTIP against WNV and ZIKV virus. DPTIP showed potent antiviral activity with EC50 values of 0.26 µM and 1.56 µM for WNV and ZIKV, respectively. In order to unravel the allosteric binding site of DPTIP in nSMase2 and the details of the interaction, computational studies have been carried out. These studies have revealed that DPTIP could block the DK switch in nSMase2. Moreover, the analysis of the residues contributing to the binding identified His463 as a crucial residue. Interestingly, the inhibitory activity of DPTIP on the H463A mutant protein supported our hypothesis. Thus, an allosteric cavity in nSMase2 has been identified that can be exploited for the development of new inhibitors with anti-flaviviral activity.

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Solomon, Tom. "Flavivirus Encephalitis." New England Journal of Medicine 351, no. 4 (July 22, 2004): 370–78. http://dx.doi.org/10.1056/nejmra030476.

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&NA;. "Flavivirus vaccine." Reactions Weekly &NA;, no. 529 (November 1994): 5. http://dx.doi.org/10.2165/00128415-199405290-00016.

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Kimura, T., M. Sasaki, M. Okumura, E. Kim, and H. Sawa. "Flavivirus Encephalitis." Veterinary Pathology 47, no. 5 (June 15, 2010): 806–18. http://dx.doi.org/10.1177/0300985810372507.

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STEPHENSON, J. "Flavivirus vaccines." Vaccine 6, no. 6 (December 1988): 471–80. http://dx.doi.org/10.1016/0264-410x(88)90095-3.

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Khristunova, Ekaterina, Elena Dorozhko, Elena Korotkova, Bohumil Kratochvil, Vlastimil Vyskocil, and Jiri Barek. "Label-Free Electrochemical Biosensors for the Determination of Flaviviruses: Dengue, Zika, and Japanese Encephalitis." Sensors 20, no. 16 (August 16, 2020): 4600. http://dx.doi.org/10.3390/s20164600.

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A highly effective way to improve prognosis of viral infectious diseases and to determine the outcome of infection is early, fast, simple, and efficient diagnosis of viral pathogens in biological fluids. Among a wide range of viral pathogens, Flaviviruses attract a special attention. Flavivirus genus includes more than 70 viruses, the most familiar being dengue virus (DENV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV). Haemorrhagic and encephalitis diseases are the most common severe consequences of flaviviral infection. Currently, increasing attention is being paid to the development of electrochemical immunological methods for the determination of Flaviviruses. This review critically compares and evaluates recent research progress in electrochemical biosensing of DENV, ZIKV, and JEV without labelling. Specific attention is paid to comparison of detection strategies, electrode materials, and analytical characteristics. The potential of so far developed biosensors is discussed together with an outlook for further development in this field.

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Eyer, Luděk, Radim Nencka, Erik de Clercq, Katherine Seley-Radtke, and Daniel Růžek. "Nucleoside analogs as a rich source of antiviral agents active against arthropod-borne flaviviruses." Antiviral Chemistry and Chemotherapy 26 (January 2018): 204020661876129. http://dx.doi.org/10.1177/2040206618761299.

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Nucleoside analogs represent the largest class of small molecule-based antivirals, which currently form the backbone of chemotherapy of chronic infections caused by HIV, hepatitis B or C viruses, and herpes viruses. High antiviral potency and favorable pharmacokinetics parameters make some nucleoside analogs suitable also for the treatment of acute infections caused by other medically important RNA and DNA viruses. This review summarizes available information on antiviral research of nucleoside analogs against arthropod-borne members of the genus Flavivirus within the family Flaviviridae, being primarily focused on description of nucleoside inhibitors of flaviviral RNA-dependent RNA polymerase, methyltransferase, and helicase/NTPase. Inhibitors of intracellular nucleoside synthesis and newly discovered nucleoside derivatives with high antiflavivirus potency, whose modes of action are currently not completely understood, have drawn attention. Moreover, this review highlights important challenges and complications in nucleoside analog development and suggests possible strategies to overcome these limitations.

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Cardozo, Fátima, Alejandra Rojas, Cynthia Bernal, Luis Ferreira, Adrián Díaz, Malvina Páez, Yvalena Guillén, Marta Contigiani, and Laura Mendoza. "Implementación de un sistema de detección de flavivirus en mosquitos." Memorias del Instituto de Investigaciones en Ciencias de la Salud 19, no. 2 (August 1, 2021): 32–40. http://dx.doi.org/10.18004/mem.iics/1812-9528/2021.019.02.32.

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Los Flavivirus constituyen virus transmitidos por artrópodos, principalmente mosquitos. Pueden producir enfermedades en humanos y animales, también incluyen virus específicos de insectos que solo infectan y se replican en los insectos, no así en vertebrados. En Paraguay los virus dengue, fiebre amarilla y Zika fueron detectados en infecciones humanas, pero los estudios de flavivirus en mosquitos son aún escasos. Por ello, el objetivo del presente estudio fue implementar un sistema de detección de flavivirus en mosquitos en el IICS-UNA. Primero, se organizaron capacitaciones en colecta, preparación de pools y procesamiento por técnicas de RT-PCRs convencionales realizadas por expertos internacionales a profesionales locales (bioquímicos y biólogos). Además, se implementaron planillas de registro de datos y de control de transporte de muestras de los lugares de colectas hasta el IICS-UNA. Se prepararon en total 201 pools de 1 a 35 mosquitos cada uno agrupados por especie, localidad, entre otros criterios. Para asegurar la integridad del RNA extraído se realizó la detección de un control interno (Actina-1), siendo todos los pools positivos para el mismo, 91/201 pools fueron positivos para flavivirus. Se realizó la secuenciación de 19/91 pools positivos para flavivirus identificándose flavivirus de insectos (detectándose principalmente Culex Flavivirus, cell fusing agents Flavivirus y Kamiti river virus), evidenciando la elevada distribución de estos virus. Estos resultados demuestran que fue factible implementar el sistema de detección de flavivirus en mosquitos, lo cual podría contribuir a fortalecer la vigilancia y control de estas virosis, así como el conocimiento sobre la importancia ecológica de flavivirus de insectos.

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Munawar, Ali, Steven Beelen, Ahmad Munawar, Eveline Lescrinier, and Sergei Strelkov. "Discovery of Novel Druggable Sites on Zika Virus NS3 Helicase Using X-ray Crystallography-Based Fragment Screening." International Journal of Molecular Sciences 19, no. 11 (November 20, 2018): 3664. http://dx.doi.org/10.3390/ijms19113664.

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The flavivirus family contains several important human pathogens, such as Zika virus (ZIKV), dengue, West Nile, and Yellow Fever viruses, that collectively lead to a large, global disease burden. Currently, there are no approved medicines that can target these viruses. The sudden outbreak of ZIKV infections in 2015–2016 posed a serious threat to global public health. While the epidemic has receded, persistent reservoirs of ZIKV infection can cause reemergence. Here, we have used X-ray crystallography-based screening to discover two novel sites on ZIKV NS3 helicase that can bind drug-like fragments. Both sites are structurally conserved in other flaviviruses, and mechanistically significant. The binding poses of four fragments, two for each of the binding sites, were characterized at atomic precision. Site A is a surface pocket on the NS3 helicase that is vital to its interaction with NS5 polymerase and formation of the flaviviral replication complex. Site B corresponds to a flexible, yet highly conserved, allosteric site at the intersection of the three NS3 helicase domains. Saturation transfer difference nuclear magnetic resonance (NMR) experiments were additionally used to evaluate the binding strength of the fragments, revealing dissociation constants (KD) in the lower mM range. We conclude that the NS3 helicase of flaviviruses is a viable drug target. The data obtained open opportunities towards structure-based design of first-in-class anti-ZIKV compounds, as well as pan-flaviviral therapeutics.

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Löhr, Kristina, John E. Knox, Wai Yee Phong, Ngai Ling Ma, Zheng Yin, Aruna Sampath, Sejal J. Patel, et al. "Yellow fever virus NS3 protease: peptide-inhibition studies." Journal of General Virology 88, no. 8 (August 1, 2007): 2223–27. http://dx.doi.org/10.1099/vir.0.82735-0.

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A recombinant form of yellow fever virus (YFV) NS3 protease, linked via a nonapeptide to the minimal NS2B co-factor sequence (CF40-gly-NS3pro190), was expressed in Escherichia coli and shown to be catalytically active. It efficiently cleaved the fluorogenic tetrapeptide substrate Bz-norleucine-lysine-arginine-arginine-AMC, which was previously optimized for dengue virus NS2B/3 protease. A series of small peptidic inhibitors based on this substrate sequence readily inhibited its enzymic activity. To understand the structure–activity relationship of the inhibitors, they were docked into a homology model of the YFV NS2B/NS3 protease structure. The results revealed that the P1 and P2 positions are most important for inhibitor binding, whilst the P3 and P4 positions have much less effect. These findings indicate that the characteristics of YFV protease are very similar to those reported for dengue and West Nile virus proteases, and suggest that pan-flavivirus NS3 protease drugs may be developed for flaviviral diseases.

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Radichev, Ilian, Sergey A. Shiryaev, Alexander E. Aleshin, Boris I. Ratnikov, Jeffrey W. Smith, Robert C. Liddington, and Alex Y. Strongin. "Structure-based mutagenesis identifies important novel determinants of the NS2B cofactor of the West Nile virus two-component NS2B–NS3 proteinase." Journal of General Virology 89, no. 3 (March 1, 2008): 636–41. http://dx.doi.org/10.1099/vir.0.83359-0.

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West Nile virus (WNV) is an emerging mosquito-borne flavivirus that causes neuronal damage in the absence of treatment. In many flaviviruses, including WNV, the NS2B cofactor promotes the productive folding and the functional activity of the two-component NS3 (pro)teinase. Based on an analysis of the NS2B–NS3pro structure, we hypothesized that the G22 residue and the negatively charged patch D32DD34 of NS2B were part of an important configuration required for NS2B–NS3pro activity. Our experimental data confirmed that G22 and D32DD34 substitution for S and AAA, respectively, inactivated NS2B–NS3pro. An additional D42G mutant, which we designed as a control, had no dramatic effect on either the catalytic activity or self-proteolysis of NS2B–NS3pro. Because of the significant level of homology in flaviviral NS2B–NS3pro, our results will be useful for the development of specific allosteric inhibitors designed to interfere with the productive interactions of NS2B with NS3pro.

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Huang, Yan-Jang, Stephen Higgs, Kate Horne, and Dana Vanlandingham. "Flavivirus-Mosquito Interactions." Viruses 6, no. 11 (November 24, 2014): 4703–30. http://dx.doi.org/10.3390/v6114703.

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CHANG, GWONG-JEN J., BRENT S. DAVIS, ANN R. HUNT, DEREK A. HOLMES, and GORO KUNO. "Flavivirus DNA Vaccines." Annals of the New York Academy of Sciences 951, no. 1 (January 25, 2006): 272–85. http://dx.doi.org/10.1111/j.1749-6632.2001.tb02703.x.

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Wang, Qing-Yin, and Pei-Yong Shi. "Flavivirus Entry Inhibitors." ACS Infectious Diseases 1, no. 9 (July 23, 2015): 428–34. http://dx.doi.org/10.1021/acsinfecdis.5b00066.

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Dong, Hongping, Katja Fink, Roland Züst, Siew Pheng Lim, Cheng-Feng Qin, and Pei-Yong Shi. "Flavivirus RNA methylation." Journal of General Virology 95, no. 4 (April 1, 2014): 763–78. http://dx.doi.org/10.1099/vir.0.062208-0.

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The 5′ end of eukaryotic mRNA contains the type-1 (m7GpppNm) or type-2 (m7GpppNmNm) cap structure. Many viruses have evolved various mechanisms to develop their own capping enzymes (e.g. flavivirus and coronavirus) or to ‘steal’ caps from host mRNAs (e.g. influenza virus). Other viruses have developed ‘cap-mimicking’ mechanisms by attaching a peptide to the 5′ end of viral RNA (e.g. picornavirus and calicivirus) or by having a complex 5′ RNA structure (internal ribosome entry site) for translation initiation (e.g. picornavirus, pestivirus and hepacivirus). Here we review the diverse viral RNA capping mechanisms. Using flavivirus as a model, we summarize how a single methyltransferase catalyses two distinct N-7 and 2′-O methylations of viral RNA cap in a sequential manner. For antiviral development, a structural feature unique to the flavivirus methyltransferase was successfully used to design selective inhibitors that block viral methyltransferase without affecting host methyltransferases. Functionally, capping is essential for prevention of triphosphate-triggered innate immune activation; N-7 methylation is critical for enhancement of viral translation; and 2′-O methylation is important for subversion of innate immune response during viral infection. Flaviviruses defective in 2′-O methyltransferase are replicative, but their viral RNAs lack 2′-O methylation and are recognized and eliminated by the host immune response. Such mutant viruses could be rationally designed as live attenuated vaccines. This concept has recently been proved with Japanese encephalitis virus and dengue virus. The findings obtained with flavivirus should be applicable to other RNA viruses.

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Stiasny, Karin, and Franz X. Heinz. "Flavivirus membrane fusion." Journal of General Virology 87, no. 10 (October 1, 2006): 2755–66. http://dx.doi.org/10.1099/vir.0.82210-0.

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Flavivirus membrane fusion is mediated by a class II viral fusion protein, the major envelope protein E, and the fusion process is extremely fast and efficient. Understanding of the underlying mechanisms has been advanced significantly by the determination of E protein structures in their pre- and post-fusion conformations and by the elucidation of the quarternary organization of E proteins in the viral envelope. In this review, these structural data are discussed in the context of functional and biochemical analyses of the flavivirus fusion mechanism and its characteristics are compared with those of other class II- and class I-driven fusion processes.

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Gack, Michaela U. "TRIMming Flavivirus Infection." Cell Host & Microbe 10, no. 3 (September 2011): 175–77. http://dx.doi.org/10.1016/j.chom.2011.08.012.

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Sips, Gregorius J., Jan Wilschut, and Jolanda M. Smit. "Neuroinvasive flavivirus infections." Reviews in Medical Virology 22, no. 2 (November 16, 2011): 69–87. http://dx.doi.org/10.1002/rmv.712.

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Crill, Wayne D., and Gwong-Jen J. Chang. "Localization and Characterization of Flavivirus Envelope Glycoprotein Cross-Reactive Epitopes." Journal of Virology 78, no. 24 (December 15, 2004): 13975–86. http://dx.doi.org/10.1128/jvi.78.24.13975-13986.2004.

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ABSTRACT The flavivirus E glycoprotein, the primary antigen that induces protective immunity, is essential for membrane fusion and mediates binding to cellular receptors. Human flavivirus infections stimulate virus species-specific as well as flavivirus cross-reactive immune responses. Flavivirus cross-reactive antibodies in human sera create a serious problem for serodiagnosis, especially for secondary flavivirus infections, due to the difficulty of differentiating primary from secondary cross-reactive serum antibodies. The presence of subneutralizing levels of flavivirus cross-reactive serum antibodies may result in a dramatic increase in the severity of secondary flavivirus infections via antibody-dependent enhancement. An understanding of flavivirus E-glycoprotein cross-reactive epitopes is therefore critical for improving public health responses to these serious diseases. We identified six E-glycoprotein residues that are incorporated into three distinct flavivirus cross-reactive epitopes. Two of these epitopes which are recognized by distinct monoclonal antibodies contain overlapping continuous residues located within the highly conserved fusion peptide. The third epitope consists of discontinuous residues that are structurally related to the strictly conserved tryptophan at dengue virus serotype 2 E-glycoprotein position 231.

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Klaitong, Paeka, and Duncan R. Smith. "Roles of Non-Structural Protein 4A in Flavivirus Infection." Viruses 13, no. 10 (October 15, 2021): 2077. http://dx.doi.org/10.3390/v13102077.

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Infections with viruses in the genus Flavivirus are a worldwide public health problem. These enveloped, positive sense single stranded RNA viruses use a small complement of only 10 encoded proteins and the RNA genome itself to remodel host cells to achieve conditions favoring viral replication. A consequence of the limited viral armamentarium is that each protein exerts multiple cellular effects, in addition to any direct role in viral replication. The viruses encode four non-structural (NS) small transmembrane proteins (NS2A, NS2B, NS4A and NS4B) which collectively remain rather poorly characterized. NS4A is a 16kDa membrane associated protein and recent studies have shown that this protein plays multiple roles, including in membrane remodeling, antagonism of the host cell interferon response, and in the induction of autophagy, in addition to playing a role in viral replication. Perhaps most importantly, NS4A has been implicated as playing a critical role in fetal developmental defects seen as a consequence of Zika virus infection during pregnancy. This review provides a comprehensive overview of the multiple roles of this small but pivotal protein in mediating the pathobiology of flaviviral infections.

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Thibodeaux, Brett A., Amanda N. Panella, and John T. Roehrig. "Development of Human-Murine Chimeric Immunoglobulin G for Use in the Serological Detection of Human Flavivirus and Alphavirus Antibodies." Clinical and Vaccine Immunology 17, no. 10 (August 25, 2010): 1617–23. http://dx.doi.org/10.1128/cvi.00097-10.

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ABSTRACT Diagnosis of human arboviral infections relies heavily on serological techniques such as the immunoglobulin M (IgM) antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) and the indirect IgG ELISA. Broad application of these assays is hindered by the lack of standardized positive human control sera that react with a wide variety of flaviviruses (e.g., dengue, West Nile, yellow fever, Japanese encephalitis, Saint Louis encephalitis, and Powassan viruses), or alphaviruses (e.g., Eastern equine encephalitis, Western equine encephalitis, Venezuelan equine encephalitis, and chikungunya viruses) that can cause human disease. We have created human-murine chimeric monoclonal antibodies (cMAbs) by combining the variable regions of flavivirus (6B6C-1) or alphavirus (1A4B-6) broadly cross-reactive murine MAbs (mMAbs) with the constant region of human IgG1. These cMAbs may be used as standardized reagents capable of replacing human infection-immune-positive control sera in indirect IgG ELISA for diagnosis of all human flaviviral or alphaviral infections. The IgG cMAbs secreted from plasmid-transformed Sp2/0-Ag14 cells had serological activity identical to that of the parent mMAbs, as measured by ELISA using multiple flaviviruses or alphaviruses.

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Zhang, Bo, Hongping Dong, Yangsheng Zhou, and Pei-Yong Shi. "Genetic Interactions among the West Nile Virus Methyltransferase, the RNA-Dependent RNA Polymerase, and the 5′ Stem-Loop of Genomic RNA." Journal of Virology 82, no. 14 (April 30, 2008): 7047–58. http://dx.doi.org/10.1128/jvi.00654-08.

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Abstract:

ABSTRACT Flavivirus methyltransferase catalyzes both guanine N7 and ribose 2′-OH methylations of the viral RNA cap (GpppA-RNA→m7GpppAm-RNA). The methyltransferase is physically linked to an RNA-dependent RNA polymerase (RdRp) in the flaviviral NS5 protein. Here, we report genetic interactions of West Nile virus (WNV) methyltransferase with the RdRp and the 5′-terminal stem-loop of viral genomic RNA. Genome-length RNAs, containing amino acid substitutions of D146 (a residue essential for both cap methylations) in the methyltransferase, were transfected into BHK-21 cells. Among the four mutant RNAs (D146L, D146P, D146R, and D146S), only D146S RNA generated viruses in transfected cells. Sequencing of the recovered viruses revealed that, besides the D146S change in the methyltransferase, two classes of compensatory mutations had reproducibly emerged. Class 1 mutations were located in the 5′-terminal stem-loop of the genomic RNA (a G35U substitution or U38 insertion). Class 2 mutations resided in NS5 (K61Q in methyltransferase and W751R in RdRp). Mutagenesis analysis, using a genome-length RNA and a replicon of WNV, demonstrated that the D146S substitution alone was lethal for viral replication; however, the compensatory mutations rescued replication, with the highest rescuing efficiency occurring when both classes of mutations were present. Biochemical analysis showed that a low level of N7 methylation of the D146S methyltransferase is essential for the recovery of adaptive viruses. The methyltransferase K61Q mutation facilitates viral replication through improved N7 methylation activity. The RdRp W751R mutation improves viral replication through an enhanced polymerase activity. Our results have clearly established genetic interactions among flaviviral methyltransferase, RdRp, and the 5′ stem-loop of the genomic RNA.

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Journal articles on the topic 'Flaviviru'

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