Journal articles on the topic 'Flaviviruses'
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1
Heinz, Franz X., and Karin Stiasny. "Flaviviruses and flavivirus vaccines." Vaccine 30, no. 29 (June 2012): 4301–6. http://dx.doi.org/10.1016/j.vaccine.2011.09.114.
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Huhtamo, Eili, Niina Putkuri, Satu Kurkela, Tytti Manni, Antti Vaheri, Olli Vapalahti, and Nathalie Y. Uzcátegui. "Characterization of a Novel Flavivirus from Mosquitoes in Northern Europe That Is Related to Mosquito-Borne Flaviviruses of the Tropics." Journal of Virology 83, no. 18 (July 1, 2009): 9532–40. http://dx.doi.org/10.1128/jvi.00529-09.
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ABSTRACT A novel flavivirus was isolated from mosquitoes in Finland, representing the first mosquito-borne flavivirus from Northern Europe. The isolate, designated Lammi virus (LAMV), was antigenically cross-reactive with other flaviviruses and exhibited typical flavivirus morphology as determined by electron microscopy. The genomic sequence of LAMV was highly divergent from the recognized flaviviruses, and yet the polyprotein properties resembled those of mosquito-borne flaviviruses. Phylogenetic analysis of the complete coding sequence showed that LAMV represented a distinct lineage related to the Aedes sp.-transmitted human pathogenic flaviviruses, similarly to the newly described Nounané virus (NOUV), a flavivirus from Africa (S. Junglen et al., J. Virol. 83:4462-4468, 2009). Despite the low sequence homology, LAMV and NOUV were phylogenetically grouped closely, likely representing separate species of a novel group of flaviviruses. Despite the biological properties preferring replication in mosquito cells, the genetic relatedness of LAMV to viruses associated with vertebrate hosts warrants a search for disease associations.
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Alkan, Cigdem, Sonia Zapata, Laurence Bichaud, Grégory Moureau, Philippe Lemey, Andrew E. Firth, Tamara S. Gritsun, et al. "Ecuador Paraiso Escondido Virus, a New Flavivirus Isolated from New World Sand Flies in Ecuador, Is the First Representative of a Novel Clade in the Genus Flavivirus." Journal of Virology 89, no. 23 (September 9, 2015): 11773–85. http://dx.doi.org/10.1128/jvi.01543-15.
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ABSTRACTA new flavivirus, Ecuador Paraiso Escondido virus (EPEV), named after the village where it was discovered, was isolated from sand flies (Psathyromyia abonnenci, formerlyLutzomyia abonnenci) that are unique to the New World. This represents the first sand fly-borne flavivirus identified in the New World. EPEV exhibited a typical flavivirus genome organization. Nevertheless, the maximum pairwise amino acid sequence identity with currently recognized flaviviruses was 52.8%. Phylogenetic analysis of the complete coding sequence showed that EPEV represents a distinct clade which diverged from a lineage that was ancestral to the nonvectored flaviviruses Entebbe bat virus, Yokose virus, and Sokoluk virus and also theAedes-associated mosquito-borne flaviviruses, which include yellow fever virus, Sepik virus, Saboya virus, and others. EPEV replicated in C6/36 mosquito cells, yielding high infectious titers, but failed to reproduce either in vertebrate cell lines (Vero, BHK, SW13, and XTC cells) or in suckling mouse brains. This surprising result, which appears to eliminate an association with vertebrate hosts in the life cycle of EPEV, is discussed in the context of the evolutionary origins of EPEV in the New World.IMPORTANCEThe flaviviruses are rarely (if ever) vectored by sand fly species, at least in the Old World. We have identified the first representative of a sand fly-associated flavivirus, Ecuador Paraiso Escondido virus (EPEV), in the New World. EPEV constitutes a novel clade according to current knowledge of the flaviviruses. Phylogenetic analysis of the virus genome showed that EPEV roots theAedes-associated mosquito-borne flaviviruses, including yellow fever virus. In light of this new discovery, the New World origin of EPEV is discussed together with that of the other flaviviruses.
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Dong, Hao-Long, Mei-Juan He, Qing-Yang Wang, Jia-Zhen Cui, Zhi-Li Chen, Xiang-Hua Xiong, Lian-Cheng Zhang, et al. "Rapid Generation of Recombinant Flaviviruses Using Circular Polymerase Extension Reaction." Vaccines 11, no. 7 (July 17, 2023): 1250. http://dx.doi.org/10.3390/vaccines11071250.
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The genus Flavivirus is a group of arthropod-borne single-stranded RNA viruses, which includes important human and animal pathogens such as Japanese encephalitis virus (JEV), Zika virus (ZIKV), Dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), and Tick-borne encephalitis virus (TBEV). Reverse genetics has been a useful tool for understanding biological properties and the pathogenesis of flaviviruses. However, the conventional construction of full-length infectious clones for flavivirus is time-consuming and difficult due to the toxicity of the flavivirus genome to E. coli. Herein, we applied a simple, rapid, and bacterium-free circular polymerase extension reaction (CPER) method to synthesize recombinant flaviviruses in vertebrate cells as well as insect cells. We started with the de novo synthesis of the JEV vaccine strain SA-14-14-2 in Vero cells using CPER, and then modified the CPER method to recover insect-specific flaviviruses (ISFs) in mosquito C6/36 cells. Chimeric Zika virus (ChinZIKV) based on the Chaoyang virus (CYV) backbone and the Culex flavivirus reporter virus expressing green fluorescent protein (CxFV-GFP) were subsequently rescued in C6/36 cells. CPER is a simple method for the rapid generation of flaviviruses and other potential RNA viruses. A CPER-based recovery system for flaviviruses of different host ranges was established, which would facilitate the development of countermeasures against flavivirus outbreaks in the future.
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Cook, Shelley, Gregory Moureau, Andrew Kitchen, Ernest A. Gould, Xavier de Lamballerie, Edward C. Holmes, and Ralph E. Harbach. "Molecular evolution of the insect-specific flaviviruses." Journal of General Virology 93, no. 2 (February 1, 2012): 223–34. http://dx.doi.org/10.1099/vir.0.036525-0.
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There has been an explosion in the discovery of ‘insect-specific’ flaviviruses and/or their related sequences in natural mosquito populations. Herein we review all ‘insect-specific’ flavivirus sequences currently available and conduct phylogenetic analyses of both the ‘insect-specific’ flaviviruses and available sequences of the entire genus Flavivirus. We show that there is no statistical support for virus–mosquito co-divergence, suggesting that the ‘insect-specific’ flaviviruses may have undergone multiple introductions with frequent host switching. We discuss potential implications for the evolution of vectoring within the family Flaviviridae. We also provide preliminary evidence for potential recombination events in the history of cell fusing agent virus. Finally, we consider priorities and guidelines for future research on ‘insect-specific’ flaviviruses, including the vast potential that exists for the study of biodiversity within a range of potential hosts and vectors, and its effect on the emergence and maintenance of the flaviviruses.
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Gibbs, Tristan, and David J. Speers. "Neurological disease caused by flavivirus infections." Microbiology Australia 39, no. 2 (2018): 99. http://dx.doi.org/10.1071/ma18029.
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The Flavivirus genus contains dozens of species with varying geographical distributions. Most flavivirus infections in humans are asymptomatic or manifest as a non-specific febrile illness, sometimes accompanied by rash or arthralgia. Certain species are more commonly associated with neurological disease and may be termed neurotropic flaviviruses. Several flaviviruses endemic to Australia and our near northern neighbours are neurotropic, such as Murray Valley encephalitis virus, West Nile (Kunjin) virus and Japanese encephalitis virus. Flavivirus neurological disease ranges from self-limiting meningitis to fulminant encephalitis causing permanent debilitating neurological sequelae or death. The recent Zika virus outbreak in South America has highlighted the dramatic effects of flavivirus neurotropism on the developing brain. This article focuses on the neurotropic flaviviruses endemic to Australia and those of international significance.
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Liao, Ching-Len, Yi-Ling Lin, Bi-Ching Wu, Chang-Huei Tsao, Mei-Chuan Wang, Chiu-I. Liu, Yue-Ling Huang, Jui-Hui Chen, Jia-Pey Wang, and Li-Kuang Chen. "Salicylates Inhibit Flavivirus Replication Independently of Blocking Nuclear Factor Kappa B Activation." Journal of Virology 75, no. 17 (September 1, 2001): 7828–39. http://dx.doi.org/10.1128/jvi.75.17.7828-7839.2001.
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ABSTRACT Flaviviruses comprise a positive-sense RNA genome that replicates exclusively in the cytoplasm of infected cells. Whether flaviviruses require an activated nuclear factor(s) to complete their life cycle and trigger apoptosis in infected cells remains elusive. Flavivirus infections quickly activate nuclear factor kappa B (NF-κB), and salicylates have been shown to inhibit NF-κB activation. In this study, we investigated whether salicylates suppress flavivirus replication and virus-induced apoptosis in cultured cells. In a dose-dependent inhibition, we found salicylates within a range of 1 to 5 mM not only restricted flavivirus replication but also abrogated flavivirus-triggered apoptosis. However, flavivirus replication was not affected by a specific NF-κB peptide inhibitor, SN50, and a proteosome inhibitor, lactacystin. Flaviviruses also replicated and triggered apoptosis in cells stably expressing IκBα-ΔN, a dominant-negative mutant that antagonizes NF-κB activation, as readily as in wild-type BHK-21 cells, suggesting that NF-κB activation is not essential for either flavivirus replication or flavivirus-induced apoptosis. Salicylates still diminished flavivirus replication and blocked apoptosis in the same IκBα-ΔN cells. This inhibition of flaviviruses by salicylates could be partially reversed by a specific p38 mitogen-activated protein (MAP) kinase inhibitor, SB203580. Together, these results show that the mechanism by which salicylates suppress flavivirus infection may involve p38 MAP kinase activity but is independent of blocking the NF-κB pathway.
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Hou, Baohua, Hui Chen, Na Gao, and Jing An. "Cross-Reactive Immunity among Five Medically Important Mosquito-Borne Flaviviruses Related to Human Diseases." Viruses 14, no. 6 (June 2, 2022): 1213. http://dx.doi.org/10.3390/v14061213.
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Flaviviruses cause a spectrum of potentially severe diseases. Most flaviviruses are transmitted by mosquitoes or ticks and are widely distributed all over the world. Among them, several mosquito-borne flaviviruses are co-epidemic, and the similarity of their antigenicity creates abundant cross-reactive immune responses which complicate their prevention and control. At present, only effective vaccines against yellow fever and Japanese encephalitis have been used clinically, while the optimal vaccines against other flavivirus diseases are still under development. The antibody-dependent enhancement generated by cross-reactive immune responses against different serotypes of dengue virus makes the development of the dengue fever vaccine a bottleneck. It has been proposed that the cross-reactive immunity elicited by prior infection of mosquito-borne flavivirus could also affect the outcome of the subsequent infection of heterologous flavivirus. In this review, we focused on five medically important flaviviruses, and rearranged and recapitulated their cross-reactive immunity in detail from the perspectives of serological experiments in vitro, animal experiments in vivo, and human cohort studies. We look forward to providing references and new insights for the research of flavivirus vaccines and specific prevention.
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Guarido, Milehna M., Kamini Govender, Megan A. Riddin, Maarten Schrama, Erin E. Gorsich, Basil D. Brooke, Antonio Paulo Gouveia Almeida, and Marietjie Venter. "Detection of Insect-Specific Flaviviruses in Mosquitoes (Diptera: Culicidae) in Northeastern Regions of South Africa." Viruses 13, no. 11 (October 25, 2021): 2148. http://dx.doi.org/10.3390/v13112148.
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Mosquitoes in the Aedes and Culex genera are considered the main vectors of pathogenic flaviviruses worldwide. Entomological surveillance using universal flavivirus sets of primers in mosquitoes can detect not only pathogenic viruses but also insect-specific ones. It is hypothesized that insect-specific flaviviruses, which naturally infect these mosquitoes, may influence their vector competence for zoonotic arboviruses. Here, entomological surveillance was performed between January 2014 and May 2018 in five different provinces in the northeastern parts of South Africa, with the aim of identifying circulating flaviviruses. Mosquitoes were sampled using different carbon dioxide trap types. Overall, 64,603 adult mosquitoes were collected, which were screened by RT-PCR and sequencing. In total, 17 pools were found positive for insect-specific Flaviviruses in the mosquito genera Aedes (12/17, 70.59%) and Anopheles (5/17, 29.41%). No insect-specific viruses were detected in Culex species. Cell-fusing agent viruses were detected in Aedes aegypti and Aedes caballus. A range of anopheline mosquitoes, including Anopheles coustani, An. squamosus and An. maculipalpis, were positive for Culex flavivirus-like and Anopheles flaviviruses. These results confirm the presence of insect-specific flaviviruses in mosquito populations in South Africa, expands their geographical range and indicates potential mosquito species as vector species.
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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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Charlier, Nathalie, Pieter Leyssen, Cornelis W. A. Pleij, Philippe Lemey, Frédérique Billoir, Kristel Van Laethem, Anne-Mieke Vandamme, Erik De Clercq, Xavier de Lamballerie, and Johan Neyts. "Complete genome sequence of Montana Myotis leukoencephalitis virus, phylogenetic analysis and comparative study of the 3′ untranslated region of flaviviruses with no known vector." Journal of General Virology 83, no. 8 (August 1, 2002): 1875–85. http://dx.doi.org/10.1099/0022-1317-83-8-1875.
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Montana Myotis leukoencephalitis virus (MMLV), a virus isolated from bats, causes an encephalitis in small rodents reminiscent of flavivirus encephalitis in humans. The complete MMLV genome is 10690 nucleotides long and encodes a putative polyprotein of 3374 amino acids. The virus contains the same conserved motifs in genes that are believed to be interesting antiviral targets (NTPase/helicase, serine protease and RNA-dependent RNA polymerase) as flaviviruses of clinical importance. Phylogenetic analysis of the entire coding region has confirmed the classification of MMLV in the clade of the flaviviruses with no known vector (NKV) and within this clade to the Rio Bravo branch (both viruses have the bat as their vertebrate host). We have provided for the first time a comparative analysis of the RNA folding of the 3′ UTR of the NKV flaviviruses (Modoc, Rio Bravo and Apoi viruses, in addition to MMLV). Structural elements in the 3′ UTR that are preserved among other flaviviruses have been revealed, as well as elements that distinguish the NKV from the mosquito- and tick-borne flaviviruses. In particular, the pentanucleotide sequence 5′ CACAG 3′, which is conserved in all mosquito- and tick-borne flaviviruses, is replaced by the sequence 5′ C(C/U)(C/U)AG 3′ in the loop of the 3′ long stable hairpin structure of all four NKV flaviviruses. The availability of this latter sequence motif allows us to designate a virus as either an NKV or a vector-borne flavivirus.
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Calzolari, Mattia, Líbia Zé-Zé, Daniel Růžek, Ana Vázquez, Claire Jeffries, Francesco Defilippo, Hugo Costa Osório, et al. "Detection of mosquito-only flaviviruses in Europe." Journal of General Virology 93, no. 6 (June 1, 2012): 1215–25. http://dx.doi.org/10.1099/vir.0.040485-0.
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The genus Flavivirus, family Flaviviridae, includes a number of important arthropod-transmitted human pathogens such as dengue viruses, West Nile virus, Japanese encephalitis virus and yellow fever virus. In addition, the genus includes flaviviruses without a known vertebrate reservoir, which have been detected only in insects, particularly in mosquitoes, such as cell fusing agent virus, Kamiti River virus, Culex flavivirus, Aedes flavivirus, Quang Binh virus, Nakiwogo virus and Calbertado virus. Reports of the detection of these viruses with no recognized pathogenic role in humans are increasing in mosquitoes collected around the world, particularly in those sampled in entomological surveys targeting pathogenic flaviviruses. The presence of six potential flaviviruses, detected from independent European arbovirus surveys undertaken in the Czech Republic, Italy,Portugal, Spain and the UK between 2007 and 2010, is reported in this work. Whilst the Aedes flaviviruses, detected in Italy from Aedes albopictus mosquitoes, had already been isolated in Japan, the remaining five viruses have not been reported previously: one was detected in Italy, Portugal and Spain from Aedes mosquitoes (particularly from Aedes caspius), one in Portugal and Spain from Culex theileri mosquitoes, one in the Czech Republic and Italy from Aedes vexans, one in the Czech Republic from Aedes vexans and the last in the UK from Aedes cinereus. Phylogenetic analysis confirmed the close relationship of these putative viruses to other insect-only flaviviruses.
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Junglen, Sandra, Anne Kopp, Andreas Kurth, Georg Pauli, Heinz Ellerbrok, and Fabian H. Leendertz. "A New Flavivirus and a New Vector: Characterization of a Novel Flavivirus Isolated from Uranotaenia Mosquitoes from a Tropical Rain Forest." Journal of Virology 83, no. 9 (February 18, 2009): 4462–68. http://dx.doi.org/10.1128/jvi.00014-09.
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ABSTRACT A novel flavivirus was isolated from Uranotaenia mashonaensis, a mosquito genus not previously known to harbor flaviviruses. Mosquitoes were caught in the primary rain forest of the Taï National Park, Côte d'Ivoire. The novel virus, termed nounané virus (NOUV), seemed to grow only on C6/36 insect cells and not on vertebrate cells. Typical enveloped flavivirus-like particles of 60 to 65 nm in diameter were detected by electron microscopy in the cell culture supernatant of infected cells. The full genome was sequenced, and potential cleavage and glycosylation sites and cysteine residues were identified, suggesting that the processing of the NOUV polyprotein is similar to that of other flaviviruses. Phylogenetic analyses of the whole polyprotein and the NS3 protein showed that the virus forms a distinct cluster within the clade of mosquito-borne flaviviruses. Only a distant relationship to other known flaviviruses was found, indicating that NOUV is a novel lineage within the Flaviviridae.
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Wahaab, Abdul, Bahar E. Mustafa, Muddassar Hameed, Nigel J. Stevenson, Muhammad Naveed Anwar, Ke Liu, Jianchao Wei, Yafeng Qiu, and Zhiyong Ma. "Potential Role of Flavivirus NS2B-NS3 Proteases in Viral Pathogenesis and Anti-flavivirus Drug Discovery Employing Animal Cells and Models: A Review." Viruses 14, no. 1 (December 28, 2021): 44. http://dx.doi.org/10.3390/v14010044.
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Flaviviruses are known to cause a variety of diseases in humans in different parts of the world. There are very limited numbers of antivirals to combat flavivirus infection, and therefore new drug targets must be explored. The flavivirus NS2B-NS3 proteases are responsible for the cleavage of the flavivirus polyprotein, which is necessary for productive viral infection and for causing clinical infections; therefore, they are a promising drug target for devising novel drugs against different flaviviruses. This review highlights the structural details of the NS2B-NS3 proteases of different flaviviruses, and also describes potential antiviral drugs that can interfere with the viral protease activity, as determined by various studies. Moreover, optimized in vitro reaction conditions for studying the NS2B-NS3 proteases of different flaviviruses may vary and have been incorporated in this review. The increasing availability of the in silico and crystallographic/structural details of flavivirus NS2B-NS3 proteases in free and drug-bound states can pave the path for the development of promising antiflavivirus drugs to be used in clinics. However, there is a paucity of information available on using animal cells and models for studying flavivirus NS2B-NS3 proteases, as well as on the testing of the antiviral drug efficacy against NS2B-NS3 proteases. Therefore, on the basis of recent studies, an effort has also been made to propose potential cellular and animal models for the study of flavivirus NS2B-NS3 proteases for the purposes of exploring flavivirus pathogenesis and for testing the efficacy of possible drugs targets, in vitro and in vivo.
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Singh, Rekha, and Sharone Green. "Enhanced CD8+ T-cell immunity following sequential flavivirus vaccines (39.19)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 39.19. http://dx.doi.org/10.4049/jimmunol.184.supp.39.19.
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Abstract Flaviviruses are arthropod-borne, RNA viruses of the Flaviviridae family. Flavivirus antigen-specific CD8+ T-cells are important in virus clearance. Primary exposure to a virus causes priming of CD8+ T-cells by virus-derived immunodominant peptides, leading to clonal differentiation and proliferation of effector cells followed by contraction and memory generation. ChimeriVax™ Flavivirus vaccines contain the nonstructural genes of the yellow fever (YF) vaccine and the prM and E genes of heterologous flaviviruses such as Japanese encephalitis (JE) and West Nile (WN) viruses. These chimeric vaccines induce both humoral and cell mediated immunity, however their potential to generate cross-reactive CD8+ T-cell responses to heterologous flaviviruses has not been investigated. In this study, mice were immunized with YF, YF/JE, or YF/WN vaccines followed by secondary homologous or heterologous immunization. We examined the hierarchy and function of CD8+ T-cell responses to a variable envelope epitope with those directed against a conserved immunodominant YF NS3 epitope. Using cell based immunological assays (ELISPOT and ICS), we found that the secondary immunization with heterologous chimeric flavivirus vaccines generate an enhanced cross-reactive CD8+ T-cell response that was dependent on the sequence of the primary immunization. Present results suggest that controlled exposure to multiple related flavivirus vaccines may lead to enhanced protection against related flaviviruses.
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Castilho, Leda R., Nathalia R. Mattos, Wallace S. Abreu, and Melissa L. E. Gutarra. "Virus-Like Particles (VLPs) as Important Tools for Flavivirus Vaccine Development." Biologics 2, no. 4 (October 31, 2022): 226–42. http://dx.doi.org/10.3390/biologics2040018.
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Flaviviruses, such as dengue, zika, yellow fever, West Nile, and Japanese encephalitis virus, are RNA viruses belonging to the Flaviviridae family (genus Flavivirus). They represent an important global health concern, since most areas of the world are endemic for at least one of these viruses. Although vaccines for five flaviviruses currently exist, there is a need for new vaccines to protect from established, emerging, and reemerging flaviviruses. Yellow fever vaccine shortages experienced in the last decade, combined with the risk of YFV spread to Asia and the restrictions of vaccine administration to certain population segments, show that even when a highly efficacious vaccine is available, new and improved vaccines might be needed. Virus-like particles (VLPs) are multiprotein structures that mimic the virus, but do not contain its genetic material. As such, VLPs have an excellent track record of strong immunogenicity and high safety, dating back to the introduction of the first recombinant hepatitis B vaccine in the 1980s. Flavivirus-like particles (FVLPs) have been extensively studied, especially for DENV, JEV, and ZIKV, and could give rise to next-generation recombinant subunit flavivirus vaccines based on VLPs incorporating molecular features intended to ensure high efficacy and minimize the risk of antibody-dependent enhancement (ADE) upon infection with other flaviviruses.
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Zhang, Naru, Chaoqun Li, Shibo Jiang, and Lanying Du. "Recent Advances in the Development of Virus-Like Particle-Based Flavivirus Vaccines." Vaccines 8, no. 3 (August 27, 2020): 481. http://dx.doi.org/10.3390/vaccines8030481.
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Flaviviruses include several medically important viruses, such as Zika virus (ZIKV), Dengue virus (DENV), West Nile virus (WNV) and Japanese encephalitis virus (JEV). They have expanded in geographic distribution and refocused international attention in recent years. Vaccination is one of the most effective public health strategies for combating flavivirus infections. In this review, we summarized virus-like particle (VLP)-based vaccines against the above four mentioned flaviviruses. Potential strategies to improve the efficacy of VLP-based flavivirus vaccines were also illustrated. The applications of flavivirus VLPs as tools for viral detection and antiviral drug screening were finally proposed.
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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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Reis, Vinicius Pinho dos, Markus Keller, Katja Schmidt, Rainer Günter Ulrich, and Martin Hermann Groschup. "αVβ3 Integrin Expression Is Essential for Replication of Mosquito and Tick-Borne Flaviviruses in Murine Fibroblast Cells." Viruses 14, no. 1 (December 23, 2021): 18. http://dx.doi.org/10.3390/v14010018.
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The Flavivirus genus includes a number of important viruses that are pathogenic to humans and animals and are responsible for outbreaks across the globe. Integrins, a family of heterodimeric transmembrane molecules expressed in all nucleated cells mediate critical functions of cell physiology and cell cycle. Integrins were previously postulated to be involved in flavivirus entry and to modulate flavivirus replication efficiency. In the present study, mouse embryonic fibroblasts (MEF), lacking the expression of αVβ3 integrin (MEF-αVβ3−/−), were infected with four different flaviviruses, namely yellow fever virus (YFV), West Nile virus (WNV), Usutu virus (USUV) and Langat virus (LGTV). The effects of the αVβ3 integrin absence in double-knockout MEF-αVβ3−/− on flavivirus binding, internalization and replication were compared to the respective wild-type cells. Binding to the cell surface for all four flaviviruses was not affected by the ablation of αVβ3 integrin, whereas internalization of USUV and WNV was slightly affected by the loss of αVβ3 integrin expression. Most interestingly, the deletion of αVβ3 integrin strongly impaired replication of all flaviviruses with a reduction of up to 99% on virus yields and a strong reduction on flavivirus anti-genome RNA synthesis. In conclusion, our results demonstrate that αVβ3 integrin expression in flavivirus-susceptible cell lines enhances the flavivirus replication.
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Gomes da Silva, Priscilla, José Augusto Seixas dos Reis, Marcio Nogueira Rodrigues, Quézia da Silva Ardaya, and João Rodrigo Mesquita. "Serological Cross-Reactivity in Zoonotic Flaviviral Infections of Medical Importance." Antibodies 12, no. 1 (February 24, 2023): 18. http://dx.doi.org/10.3390/antib12010018.
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Flaviviruses are enveloped RNA viruses from the family Flaviviridae that comprise many important human pathogenic arboviruses such as Yellow Fever, Dengue, and Zika viruses. Because they belong to the same genus, these viruses show sequence and structural homology among them, which results in serological cross-reactivity. Upon infection, the immune system produces both species-specific and cross-reactive antibodies, and depending on the virus, in a successive flavivirus infection, cross-reactive antibodies either enhance protection or exacerbate the disease—the latter usually due to antibody-dependent enhancement. These antigenic relationships between different flaviviruses that lead to serological cross-reactivity make them difficult to be identified through serological methods, especially when it comes to successive flavivirus infections. We present here an overview of the main structural, epidemiological, and immunological aspects of flaviviruses, highlighting the role of neutralizing antibodies in fighting viral infections and in the “original antigenic sin” problem. Finally, we draw attention to the importance of developing a rapid serological diagnostic test for flaviviruses with high sensitivity and specificity, especially when considering that cross-reactive immunity can influence the outcome of these infections.
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Qian, Xijing, and Zhongtian Qi. "Mosquito-Borne Flaviviruses and Current Therapeutic Advances." Viruses 14, no. 6 (June 5, 2022): 1226. http://dx.doi.org/10.3390/v14061226.
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Mosquito-borne flavivirus infections affect approximately 400 million people worldwide each year and are global threats to public health. The common diseases caused by such flaviviruses include West Nile, yellow fever, dengue, Zika infection and Japanese encephalitis, which may result in severe symptoms and disorders of multiple organs or even fatal outcomes. Till now, no specific antiviral agents are commercially available for the treatment of the diseases. Numerous strategies have been adopted to develop novel and promising inhibitors against mosquito-borne flaviviruses, including drugs targeting the critical viral components or essential host factors during infection. Research advances in antiflaviviral therapy might optimize and widen the treatment options for flavivirus infection. This review summarizes the current developmental progresses and involved molecular mechanisms of antiviral agents against mosquito-borne flaviviruses.
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Kenney, Joan L., Owen D. Solberg, Stanley A. Langevin, and Aaron C. Brault. "Characterization of a novel insect-specific flavivirus from Brazil: potential for inhibition of infection of arthropod cells with medically important flaviviruses." Journal of General Virology 95, no. 12 (December 1, 2014): 2796–808. http://dx.doi.org/10.1099/vir.0.068031-0.
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In the past decade, there has been an upsurge in the number of newly described insect-specific flaviviruses isolated pan-globally. We recently described the isolation of a novel flavivirus (tentatively designated ‘Nhumirim virus’; NHUV) that represents an example of a unique subset of apparently insect-specific viruses that phylogenetically affiliate with dual-host mosquito-borne flaviviruses despite appearing to be limited to replication in mosquito cells. We characterized the in vitro growth potential and 3′ untranslated region (UTR) sequence homology with alternative flaviviruses, and evaluated the virus’s capacity to suppress replication of representative Culex spp.-vectored pathogenic flaviviruses in mosquito cells. Only mosquito cell lines were found to support NHUV replication, further reinforcing the insect-specific phenotype of this virus. Analysis of the sequence and predicted RNA secondary structures of the 3′ UTR indicated NHUV to be most similar to viruses within the yellow fever serogroup and Japanese encephalitis serogroup, and viruses in the tick-borne flavivirus clade. NHUV was found to share the fewest conserved sequence elements when compared with traditional insect-specific flaviviruses. This suggests that, despite apparently being insect specific, this virus probably diverged from an ancestral mosquito-borne flavivirus. Co-infection experiments indicated that prior or concurrent infection of mosquito cells with NHUV resulted in a significant reduction in virus production of West Nile virus (WNV), St Louis encephalitis virus (SLEV) and Japanese encephalitis virus. The inhibitory effect was most effective against WNV and SLEV with over a 106-fold and 104-fold reduction in peak titres, respectively.
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Berneck, Beatrice Sarah, Alexandra Rockstroh, Jasmin Fertey, Thomas Grunwald, and Sebastian Ulbert. "A Recombinant Zika Virus Envelope Protein with Mutations in the Conserved Fusion Loop Leads to Reduced Antibody Cross-Reactivity upon Vaccination." Vaccines 8, no. 4 (October 13, 2020): 603. http://dx.doi.org/10.3390/vaccines8040603.
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Zika virus (ZIKV) is a zoonotic, human pathogenic, and mosquito-borne flavivirus. Its distribution is rapidly growing worldwide. Several attempts to develop vaccines for ZIKV are currently ongoing. Central to most vaccination approaches against flavivirus infections is the envelope (E) protein, which is the major target of neutralizing antibodies. Insect-cell derived, recombinantly expressed variants of E from the flaviviruses West Nile and Dengue virus have entered clinical trials in humans. Also for ZIKV, these antigens are promising vaccine candidates. Due to the structural similarity of flaviviruses, cross-reactive antibodies are induced by flavivirus antigens and have been linked to the phenomenon of antibody-dependent enhancement of infection (ADE). Especially the highly conserved fusion loop domain (FL) in the E protein is a target of such cross-reactive antibodies. In areas where different flaviviruses co-circulate and heterologous infections cannot be ruled out, this is of concern. To exclude the possibility that recombinant E proteins of ZIKV might induce ADE in infections with related flaviviruses, we performed an immunization study with an insect-cell derived E protein containing four mutations in and near the FL. Our data show that this mutant antigen elicits antibodies with equal neutralizing capacity as the wildtype equivalent. However, it induces much less serological cross-reactivity and does not cause ADE in vitro. These results indicate that mutated variants of the E protein might lead to ZIKV and other flavivirus vaccines with increased safety profiles.
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Vicenzi, Elisa, Isabel Pagani, Silvia Ghezzi, Sarah L. Taylor, Timothy R. Rudd, Marcelo A. Lima, Mark A. Skidmore, and Edwin A. Yates. "Subverting the mechanisms of cell death: flavivirus manipulation of host cell responses to infection." Biochemical Society Transactions 46, no. 3 (April 20, 2018): 609–17. http://dx.doi.org/10.1042/bst20170399.
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Viruses exploit host metabolic and defence machinery for their own replication. The flaviviruses, which include Dengue (DENV), Yellow Fever (YFV), Japanese Encephalitis (JEV), West Nile (WNV) and Zika (ZIKV) viruses, infect a broad range of hosts, cells and tissues. Flaviviruses are largely transmitted by mosquito bites and humans are usually incidental, dead-end hosts, with the notable exceptions of YFV, DENV and ZIKV. Infection by flaviviruses elicits cellular responses including cell death via necrosis, pyroptosis (involving inflammation) or apoptosis (which avoids inflammation). Flaviviruses exploit these mechanisms and subvert them to prolong viral replication. The different effects induced by DENV, WNV, JEV and ZIKV are reviewed. Host cell surface proteoglycans (PGs) bearing glycosaminoglycan (GAG) polysaccharides — heparan/chondroitin sulfate (HS/CS) — are involved in initial flavivirus attachment and during the expression of non-structural viral proteins play a role in disease aetiology. Recent work has shown that ZIKV-infected cells are protected from cell death by exogenous heparin (a GAG structurally similar to host cell surface HS), raising the possibility of further subtle involvement of HS PGs in flavivirus disease processes. The aim of this review is to synthesize information regarding DENV, WNV, JEV and ZIKV from two areas that are usually treated separately: the response of host cells to infection by flaviviruses and the involvement of cell surface GAGs in response to those infections.
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Howard-Jones, Annaleise R., David Pham, Rebecca Sparks, Susan Maddocks, Dominic E. Dwyer, Jen Kok, and Kerri Basile. "Arthropod-Borne Flaviviruses in Pregnancy." Microorganisms 11, no. 2 (February 8, 2023): 433. http://dx.doi.org/10.3390/microorganisms11020433.
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Flaviviruses are a diverse group of enveloped RNA viruses that cause significant clinical manifestations in the pregnancy and postpartum periods. This review highlights the epidemiology, pathophysiology, clinical features, diagnosis, and prevention of the key arthropod-borne flaviviruses of concern in pregnancy and the neonatal period—Zika, Dengue, Japanese encephalitis, West Nile, and Yellow fever viruses. Increased disease severity during pregnancy, risk of congenital malformations, and manifestations of postnatal infection vary widely amongst this virus family and may be quite marked. Laboratory confirmation of infection is complex, especially due to the reliance on serology for which flavivirus cross-reactivity challenges diagnostic specificity. As such, a thorough clinical history including relevant geographic exposures and prior vaccinations is paramount for accurate diagnosis. Novel vaccines are eagerly anticipated to ameliorate the impact of these flaviviruses, particularly neuroinvasive disease manifestations and congenital infection, with consideration of vaccine safety in pregnant women and children pivotal. Moving forward, the geographical spread of flaviviruses, as for other zoonoses, will be heavily influenced by climate change due to the potential expansion of vector and reservoir host habitats. Ongoing ‘One Health’ engagement across the human-animal-environment interface is critical to detect and responding to emergent flavivirus epidemics.
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AYADI, T., A. HAMMOUDA, A. POUX, T. BOULINIER, S. LECOLLINET, and S. SELMI. "Evidence of exposure of laughing doves (Spilopelia senegalensis) to West Nile and Usutu viruses in southern Tunisian oases." Epidemiology and Infection 145, no. 13 (August 14, 2017): 2808–16. http://dx.doi.org/10.1017/s0950268817001789.
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SUMMARYIt has previously been suggested that southern Tunisian oases may be suitable areas for the circulation of flaviviruses. In order to anticipate and prevent possible epidemiological spread of flaviviruses in humans and domestic animals, the ecology of their transmission in the oasis system needs to be better understood. Thus, the aim of this study was to assess the seroprevalence of anti-flavivirus antibodies in the laughing dove (Spilopelia senegalensis), an abundant resident bird in Tunisian oases. Anti-flavivirus antibodies were detected in 17% of sampled doves. Ten per cent of the total tested doves were West Nile virus (WNV) seropositive and 4% were Usutu virus (USUV) seropositive, which provides the first evidence of USUV circulation in Tunisian birds. We also found that the occurrence probability of anti-flavivirus antibodies in dove plasma increased with decreasing distance to coast, suggesting that doves inhabiting coastal oases were more exposed to flaviviruses compared with those inhabiting inland oases. We also found significantly higher antibody occurrence probability in adult doves compared with young doves, which underlines the effect of exposure time. Overall, our results suggest that the laughing dove may be used for WNV and USUV surveillance in southern Tunisia. They also stress the need for investigations combining data on birds and mosquitoes to better understand the ecological factors governing the circulation of flaviviruses in this area.
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Zheng, Xiaoyan, and Ran Wang. "Metabolomic Analysis of Key Regulatory Metabolites in the Urine of Flavivirus-Infected Mice." Journal of Tropical Medicine 2022 (June 1, 2022): 1–12. http://dx.doi.org/10.1155/2022/4663735.
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Objective. Dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV) are several important flaviviruses, and infections caused by these flaviviruses remain worldwide health problems. Different flaviviruses exhibit different biological characteristics and pathogenicity. Metabolomics is an emerging research perspective to uncover and observe the pathogenesis of certain infections. Methods. To improve the understanding of the specific metabolic changes that occur during infection with different flaviviruses, considering the principle of noninvasive sampling, this article describes our comprehensive analysis of metabolites in urine samples from the three kinds of flavivirus-infected mice using a liquid chromatography tandem mass spectrometry method to better understand their infection mechanisms. Results. The urine of DENV-, JEV-, and ZIKV-infected mice had 68, 64, and 47 different differential metabolites, respectively, compared with the urine of control mice. Among the metabolic pathways designed by these metabolites, ABC transporters, arginine and proline metabolism, and regulation of lipolysis play an important role. Furthermore, we predicted and fitted potential relationships between metabolites and pathways. Conclusions. These virus-specific altered metabolites may be associated with their unique biological properties and pathogenicity. The metabolomic analysis of urine is very important for the analysis of flavivirus infection.
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Dowd, Kimberly A., and Theodore C. Pierson. "The Many Faces of a Dynamic Virion: Implications of Viral Breathing on Flavivirus Biology and Immunogenicity." Annual Review of Virology 5, no. 1 (September 29, 2018): 185–207. http://dx.doi.org/10.1146/annurev-virology-092917-043300.
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Flaviviruses are arthropod-borne RNA viruses that are a significant threat to global health due to their widespread distribution, ability to cause severe disease in humans, and capacity for explosive spread following introduction into new regions. Members of this genus include dengue, tick-borne encephalitis, yellow fever, and Zika viruses. Vaccination has been a highly successful means to control flaviviruses, and neutralizing antibodies are an important component of a protective immune response. High-resolution structures of flavivirus structural proteins and virions, alone and in complex with antibodies, provide a detailed understanding of viral fusion mechanisms and virus-antibody interactions. However, mounting evidence suggests these structures provide only a snapshot of an otherwise structurally dynamic virus particle. The contribution of the structural ensemble arising from viral breathing to the biology, antigenicity, and immunity of flaviviruses is discussed, including implications for the development and evaluation of flavivirus vaccines.
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Shanshin, Daniil V., Sophia S. Borisevich, Alexander A. Bondar, Yuri B. Porozov, Elena A. Rukhlova, Elena V. Protopopova, Nikita D. Ushkalenko, et al. "Can Modern Molecular Modeling Methods Help Find the Area of Potential Vulnerability of Flaviviruses?" International Journal of Molecular Sciences 23, no. 14 (July 13, 2022): 7721. http://dx.doi.org/10.3390/ijms23147721.
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Flaviviruses are single-stranded RNA viruses that have emerged in recent decades and infect up to 400 million people annually, causing a variety of potentially severe pathophysiological processes including hepatitis, encephalitis, hemorrhagic fever, tissues and capillaries damage. The Flaviviridae family is represented by four genera comprising 89 known virus species. There are no effective therapies available against many pathogenic flaviviruses. One of the promising strategies for flavivirus infections prevention and therapy is the use of neutralizing antibodies (NAb) that can disable the virus particles from infecting the host cells. The envelope protein (E protein) of flaviviruses is a three-domain structure that mediates the fusion of viral and host membranes delivering the infectious material. We previously developed and characterized 10H10 mAb which interacts with the E protein of the tick-borne encephalitis virus (TBEV) and many other flaviviruses’ E proteins. The aim of this work was to analyze the structure of E protein binding sites recognized by the 10H10 antibody, which is reactive with different flavivirus species. Here, we present experimental data and 3D modeling indicating that the 10H10 antibody recognizes the amino acid sequence between the two cysteines C92-C116 of the fusion loop (FL) region of flaviviruses’ E proteins. Overall, our results indicate that the antibody-antigen complex can form a rigid or dynamic structure that provides antibody cross reactivity and efficient interaction with the fusion loop of E protein.
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Kuhn, Richard J., Alan D. T. Barrett, Aravinda M. Desilva, Eva Harris, Laura D. Kramer, Ruth R. Montgomery, Theodore C. Pierson, Alessandro Sette, and Michael S. Diamond. "A Prototype-Pathogen Approach for the Development of Flavivirus Countermeasures." Journal of Infectious Diseases 228, Supplement_6 (October 15, 2023): S398—S413. http://dx.doi.org/10.1093/infdis/jiad193.
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Abstract Flaviviruses are a genus within the Flaviviridae family of positive-strand RNA viruses and are transmitted principally through mosquito and tick vectors. These viruses are responsible for hundreds of millions of human infections worldwide per year that result in a range of illnesses from self-limiting febrile syndromes to severe neurotropic and viscerotropic diseases and, in some cases, death. A vaccine against the prototype flavivirus, yellow fever virus, has been deployed for 85 years and is highly effective. While vaccines against some medically important flaviviruses are available, others have proven challenging to develop. The emergence and spread of flaviviruses, including dengue virus and Zika virus, demonstrate their pandemic potential. This review highlights the gaps in knowledge that need to be addressed to allow for the rapid development of vaccines against emerging flaviviruses in the future.
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Yezli, Saber, Muhammad Yasir, Yara Yassin, Afnan Almazrua, Tagreed Al-Subhi, Norah Othman, Abdiasiis Omar, et al. "Lack of Zika Virus and Other Recognized Flaviviruses among the Mosquito Vectors during and Post the Hajj Mass Gathering." International Journal of Environmental Research and Public Health 18, no. 12 (June 10, 2021): 6275. http://dx.doi.org/10.3390/ijerph18126275.
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Makkah city, Kingdom of Saudi Arabia (KSA), contains many of the world’s mosquito vectors of parasitic and arboviral disease and is the site of the Hajj mass gathering. As such there is a risk of exportation and globalization of vector-borne viruses, including the re-emerging Zika virus (ZIKV). There was international concern regarding the introduction of ZIKV to KSA and potential international spread of the virus following the 2016 Hajj which took place few days after the Rio summer Olympics at the height of the ZIKV pandemic. We aimed to detect flaviviruses, including ZIKV, circulating among mosquito hosts in the city of Makkah during and post the 2016 Hajj pilgrimage. Mosquitos (adults and larvae) were sampled from 15 sites in Makkah city during and post the 2016 Hajj and identified to species by morphological keys. Mosquitos were pooled according to date of collection, location, and species. A Pan-Flaviviruses RT-PCR assay that enables identification of 51 flaviviruses species and three tentative species was used to detect flavivirus RNA directly from mosquito homogenates. Between the 10 September and 6 October 2016, 9412 female mosquitos were collected. Of these, 81.3% were Aedes aegypti, 18.6% were Culex species, and 0.1% were Anopheles species. Of the total 493 mosquito pools generated, 242 (49%) were positive by the Pan-Flaviviruses primer set. Sequence analysis revealed that none of the mosquitos carried a pathogenic flavivirus, including ZIKV, but were infected with a novel insect-specific flavivirus. We found no pathogenic flaviviruses circulating in Makkah city during and post the 2016 Hajj and no evidence of introduction of ZIKV through the pilgrimage. Enhanced vector-borne diseases surveillance, prevention, and control are crucial in KSA especially during international mass gatherings such as the annual Hajj to prevent outbreaks and the spread of viruses with epidemic and pandemic potentials.
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Nazarenko, Alina S., Mikhail F. Vorovitch, Yulia K. Biryukova, Nikolay B. Pestov, Ekaterina A. Orlova, Nickolai A. Barlev, Nadezhda M. Kolyasnikova, and Aydar A. Ishmukhametov. "Flaviviruses in AntiTumor Therapy." Viruses 15, no. 10 (September 22, 2023): 1973. http://dx.doi.org/10.3390/v15101973.
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Oncolytic viruses offer a promising approach to tumor treatment. These viruses not only have a direct lytic effect on tumor cells but can also modify the tumor microenvironment and activate antitumor immunity. Due to their high pathogenicity, flaviviruses have often been overlooked as potential antitumor agents. However, with recent advancements in genetic engineering techniques, an extensive history with vaccine strains, and the development of new attenuated vaccine strains, there has been a renewed interest in the Flavivirus genus. Flaviviruses can be genetically modified to express transgenes at acceptable levels, and the stability of such constructs has been greatly improving over the years. The key advantages of flaviviruses include their reproduction cycle occurring entirely within the cytoplasm (avoiding genome integration) and their ability to cross the blood–brain barrier, facilitating the systemic delivery of oncolytics against brain tumors. So far, the direct lytic effects and immunomodulatory activities of many flaviviruses have been widely studied in experimental animal models across various types of tumors. In this review, we delve into the findings of these studies and contemplate the promising potential of flaviviruses in oncolytic therapies.
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JAEGER, A., S. LECOLLINET, C. BECK, M. BASTIEN, M. LE CORRE, K. DELLAGI, H. PASCALIS, T. BOULINIER, and C. LEBARBENCHON. "Serological evidence for the circulation of flaviviruses in seabird populations of the western Indian Ocean." Epidemiology and Infection 144, no. 3 (July 21, 2015): 652–60. http://dx.doi.org/10.1017/s0950268815001661.
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SUMMARYBirds play a central role in the epidemiology of several flaviviruses of concern for public and veterinary health. Seabirds represent the most abundant and widespread avifauna in the western Indian Ocean and may play an important role as host reservoirs and spreaders of arthropod-borne pathogens such as flaviviruses. We report the results of a serological investigation based on blood samples collected from nine seabird species from seven islands in the Indian Ocean. Using a commercial competitive enzyme-linked immunosorbent assay directed against the prototypic West Nile flavivirus, antibodies against flaviviruses were detected in the serum of 47 of the 855 seabirds tested. They were detected in bird samples from three islands and from four bird species. Seroneutralization tests on adults and chicks suggested that great frigatebirds (Fregata minor) from Europa were infected by West Nile virus during their non-breeding period, and that Usutu virus probably circulated within bird colonies on Tromelin and on Juan de Nova. Real-time polymerase chain reactions performed on bird blood samples did not yield positive results precluding the genetic characterization of flavivirus using RNA sequencing. Our findings stress the need to further investigate flavivirus infections in arthropod vectors present in seabird colonies.
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Petruccelli, Angela, Tiziana Zottola, Gianmarco Ferrara, Valentina Iovane, Cristina Di Russo, Ugo Pagnini, and Serena Montagnaro. "West Nile Virus and Related Flavivirus in European Wild Boar (Sus scrofa), Latium Region, Italy: A Retrospective Study." Animals 10, no. 3 (March 16, 2020): 494. http://dx.doi.org/10.3390/ani10030494.
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Background: A retrospective sero-survey for evidence of West Nile virus (WNV) infection in European wild boar (Sus scorfa) was conducted in the Latium region, Italy, on stored serum samples of the period November 2011 to January 2012. Methods: Sera were collected from 168 European wild boars and screened for antibodies to WNV and other Flaviviruses by competitive enzyme linked immunosorbent assay (cELISA). All sera positive for Flavivirus antibodies by cELISA were further examined by virus neutralization test (VNT). To test the presence of Flavivirus RNA in samples, an RT-PCR was performed using a pan-Flavivirus primers pair. Results: Thirteen wild boars (7.73%) were seropositive for Flaviviruses. The hemolysis of serum samples limited the interpretation of the VNT for 7 samples, confirming the presence of specific antibody against WNV in a single European wild boar serum sample. The presence of ELISA positive/VNT negative samples suggests the occurrence of non-neutralizing antibodies against WNV or other antigen-related Flaviviruses. No samples resulted positive for Flavivirus by RT-PCR assay. Conclusion: Although a moderately high percentage of animals with specific antibody for WNV has been detected in wild boar in other surveillance studies in Europe, this has not been reported previously in Italy. Together, these data indicate that European wild boar are exposed to WNV and/or other related-Flavivirus in central Italy and confirm the usefulness of wild ungulates, as suitable Flavivirus sentinels.
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Roy, Proyasha, Sumanta Dey, Ashesh Nandy, Subhash C. Basak, and Sukhen Das. "Base Distribution in Dengue Nucleotide Sequences Differs Significantly from Other Mosquito-Borne Human-Infecting Flavivirus Members." Current Computer-Aided Drug Design 15, no. 1 (December 14, 2018): 29–44. http://dx.doi.org/10.2174/1573409914666180731090005.
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Introduction: Among the mosquito-borne human-infecting flavivirus species that include Zika, West Nile, yellow fever, Japanese encephalitis and Dengue viruses, the Zika virus is found to be closest to Dengue virus, sharing the same clade in the Flavivirus phylogenetic tree. We consider these five flaviviruses and on closer examination in our analyses, the nucleotide sequences of the Dengue viral genes (envelope and NS5) and genomes are seen to be quite widely different from the other four flaviviruses. We consider the extent of this distinction and determine the advantage and/or disadvantage such differences may confer upon the Dengue viral pathogenesis. </P><P> Methods: We have primarily used a 2D graphical representation technique to show the differences in base distributions in these five flaviviruses and subsequently, obtained quantitative estimates of the differences. Similarity/dissimilarity between the viruses based on the genes were also determined which showed that the differences with the Dengue genes are more pronounced.Results:We found that the Dengue viruses compared to the other four flaviviruses spread rapidly worldwide and became endemic in various regions with small alterations in sequence composition relative to the host populations as revealed by codon usage biases and phylogenetic examination.We conclude that the Dengue genes are indeed more widely separated from the other aforementioned mosquito-borne human-infecting flaviviruses due to excess adenine component, a feature that is sparse in the literature. Such excesses have a bearing on drug and vaccine, especially peptide vaccine, development and should be considered appropriately.
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Stefanik, Michal, James J. Valdes, Fortunatus C. Ezebuo, Jan Haviernik, Ikemefuna C. Uzochukwu, Martina Fojtikova, Jiri Salat, Ludek Eyer, and Daniel Ruzek. "FDA-Approved Drugs Efavirenz, Tipranavir, and Dasabuvir Inhibit Replication of Multiple Flaviviruses in Vero Cells." Microorganisms 8, no. 4 (April 20, 2020): 599. http://dx.doi.org/10.3390/microorganisms8040599.
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Vector-borne flaviviruses (VBFs) affect human health worldwide, but no approved drugs are available specifically to treat VBF-associated infections. Here, we performed in silico screening of a library of U.S. Food and Drug Administration-approved antiviral drugs for their interaction with Zika virus proteins. Twelve hit drugs were identified by the docking experiments and tested in cell-based antiviral assay systems. Efavirenz, tipranavir, and dasabuvir at micromolar concentrations were identified to inhibit all VBFs tested; i.e., two representatives of mosquito-borne flaviviruses (Zika and West Nile viruses) and one representative of flaviviruses transmitted by ticks (tick-borne encephalitis virus). The results warrant further research into these drugs, either individually or in combination, as possible pan-flavivirus inhibitors.
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Therkelsen, Matthew D., Thomas Klose, Frank Vago, Wen Jiang, Michael G. Rossmann, and Richard J. Kuhn. "Flaviviruses have imperfect icosahedral symmetry." Proceedings of the National Academy of Sciences 115, no. 45 (October 22, 2018): 11608–12. http://dx.doi.org/10.1073/pnas.1809304115.
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Flaviviruses assemble initially in an immature, noninfectious state and undergo extensive conformational rearrangements to generate mature virus. Previous cryo-electron microscopy (cryo-EM) structural studies of flaviviruses assumed icosahedral symmetry and showed the concentric organization of the external glycoprotein shell, the lipid membrane, and the internal nucleocapsid core. We show here that when icosahedral symmetry constraints were excluded in calculating the cryo-EM reconstruction of an immature flavivirus, the nucleocapsid core was positioned asymmetrically with respect to the glycoprotein shell. The core was positioned closer to the lipid membrane at the proximal pole, and at the distal pole, the outer glycoprotein spikes and inner membrane leaflet were either perturbed or missing. In contrast, in the asymmetric reconstruction of a mature flavivirus, the core was positioned concentric with the glycoprotein shell. The deviations from icosahedral symmetry demonstrated that the core and glycoproteins have varied interactions, which likely promotes viral assembly and budding.
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Harrison, Jessica J., Jody Hobson-Peters, Helle Bielefeldt-Ohmann, and Roy A. Hall. "Chimeric Vaccines Based on Novel Insect-Specific Flaviviruses." Vaccines 9, no. 11 (October 22, 2021): 1230. http://dx.doi.org/10.3390/vaccines9111230.
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Vector-borne flaviviruses are responsible for nearly half a billion human infections worldwide each year, resulting in millions of cases of debilitating and severe diseases and approximately 115,000 deaths. While approved vaccines are available for some of these viruses, the ongoing efficacy, safety and supply of these vaccines are still a significant problem. New technologies that address these issues and ideally allow for the safe and economical manufacture of vaccines in resource-poor countries where flavivirus vaccines are in most demand are urgently required. Preferably a new vaccine platform would be broadly applicable to all flavivirus diseases and provide new candidate vaccines for those diseases not yet covered, as well as the flexibility to rapidly pivot to respond to newly emerged flavivirus diseases. Here, we review studies conducted on novel chimeric vaccines derived from insect-specific flaviviruses that provide a potentially safe and simple system to produce highly effective vaccines against a broad spectrum of flavivirus diseases.
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Gwon, Yong-Dae, Mårten Strand, Richard Lindqvist, Emma Nilsson, Michael Saleeb, Mikael Elofsson, Anna K. Överby, and Magnus Evander. "Antiviral Activity of Benzavir-2 against Emerging Flaviviruses." Viruses 12, no. 3 (March 22, 2020): 351. http://dx.doi.org/10.3390/v12030351.
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Most flaviviruses are arthropod-borne viruses, transmitted by either ticks or mosquitoes, and cause morbidity and mortality worldwide. They are endemic in many countries and have recently emerged in new regions, such as the Zika virus (ZIKV) in South-and Central America, the West Nile virus (WNV) in North America, and the Yellow fever virus (YFV) in Brazil and many African countries, highlighting the need for preparedness. Currently, there are no antiviral drugs available to treat flavivirus infections. We have previously discovered a broad-spectrum antiviral compound, benzavir-2, with potent antiviral activity against both DNA- and RNA-viruses. Our purpose was to investigate the inhibitory activity of benzavir-2 against flaviviruses. We used a ZIKV ZsGreen-expressing vector, two lineages of wild-type ZIKV, and other medically important flaviviruses. Benzavir-2 inhibited ZIKV derived reporter gene expression with an EC50 value of 0.8 ± 0.1 µM. Furthermore, ZIKV plaque formation, progeny virus production, and viral RNA expression were strongly inhibited. In addition, 2.5 µM of benzavir-2 reduced infection in vitro in three to five orders of magnitude for five other flaviviruses: WNV, YFV, the tick-borne encephalitis virus, Japanese encephalitis virus, and dengue virus. In conclusion, benzavir-2 was a potent inhibitor of flavivirus infection, which supported the broad-spectrum antiviral activity of benzavir-2.
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Silvia, Ondine J., Geoffrey R. Shellam, and Nadezda Urosevic. "Innate resistance to flavivirus infection in mice controlled by Flv is nitric oxide-independent." Journal of General Virology 82, no. 3 (March 1, 2001): 603–7. http://dx.doi.org/10.1099/0022-1317-82-3-603.
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Innate resistance to flaviviruses in mice is active in the brain where it restricts virus replication. This resistance is controlled by a single genetic locus, Flv, located on mouse chromosome 5 near the locus encoding the neuronal form of nitric oxide synthase (Nos1). Since nitric oxide (NO) has been implicated in antiviral activity, its involvement in natural resistance to flaviviruses has been hypothesized. Here we present data on NO production before and during flavivirus infection in both brain tissue and peritoneal macrophages from two flavivirus-resistant (Flv r) and one congenic susceptible (Flv s) mouse strains. This study provides evidence that NO is not involved in the expression of flavivirus resistance controlled by Flv since: (a) there is no difference in brain tissue NO levels between susceptible and resistant mice, and (b) lipopolysaccharide-induced NO does not abrogate the difference in flavivirus replication in peritoneal macrophages from susceptible and resistant mice.
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Carro, Stephen D., and Sara Cherry. "Beyond the Surface: Endocytosis of Mosquito-Borne Flaviviruses." Viruses 13, no. 1 (December 23, 2020): 13. http://dx.doi.org/10.3390/v13010013.
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Flaviviruses are a group of positive-sense RNA viruses that are primarily transmitted through arthropod vectors and are capable of causing a broad spectrum of diseases. Many of the flaviviruses that are pathogenic in humans are transmitted specifically through mosquito vectors. Over the past century, many mosquito-borne flavivirus infections have emerged and re-emerged, and are of global importance with hundreds of millions of infections occurring yearly. There is a need for novel, effective, and accessible vaccines and antivirals capable of inhibiting flavivirus infection and ameliorating disease. The development of therapeutics targeting viral entry has long been a goal of antiviral research, but most efforts are hindered by the lack of broad-spectrum potency or toxicities associated with on-target effects, since many host proteins necessary for viral entry are also essential for host cell biology. Mosquito-borne flaviviruses generally enter cells by clathrin-mediated endocytosis (CME), and recent studies suggest that a subset of these viruses can be internalized through a specialized form of CME that has additional dependencies distinct from canonical CME pathways, and antivirals targeting this pathway have been discovered. In this review, we discuss the role and contribution of endocytosis to mosquito-borne flavivirus entry as well as consider past and future efforts to target endocytosis for therapeutic interventions.
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Zhao, Rong, Meiyue Wang, Jing Cao, Jing Shen, Xin Zhou, Deping Wang, and Jimin Cao. "Flavivirus: From Structure to Therapeutics Development." Life 11, no. 7 (June 25, 2021): 615. http://dx.doi.org/10.3390/life11070615.
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Flaviviruses are still a hidden threat to global human safety, as we are reminded by recent reports of dengue virus infections in Singapore and African-lineage-like Zika virus infections in Brazil. Therapeutic drugs or vaccines for flavivirus infections are in urgent need but are not well developed. The Flaviviridae family comprises a large group of enveloped viruses with a single-strand RNA genome of positive polarity. The genome of flavivirus encodes ten proteins, and each of them plays a different and important role in viral infection. In this review, we briefly summarized the major information of flavivirus and further introduced some strategies for the design and development of vaccines and anti-flavivirus compound drugs based on the structure of the viral proteins. There is no doubt that in the past few years, studies of antiviral drugs have achieved solid progress based on better understanding of the flavivirus biology. However, currently, there are no fully effective antiviral drugs or vaccines for most flaviviruses. We hope that this review may provide useful information for future development of anti-flavivirus drugs and vaccines.
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ISHIKAWA, Tomohiro, and Eiji KONISHI. "Flaviviruses." Uirusu 61, no. 2 (2011): 221–38. http://dx.doi.org/10.2222/jsv.61.221.
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Best, Sonja M. "Flaviviruses." Current Biology 26, no. 24 (December 2016): R1258—R1260. http://dx.doi.org/10.1016/j.cub.2016.09.029.
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Stiasny, Karin, Stefan Malafa, Stephan W. Aberle, Iris Medits, Georgios Tsouchnikas, Judith H. Aberle, Heidemarie Holzmann, and Franz X. Heinz. "Different Cross-Reactivities of IgM Responses in Dengue, Zika and Tick-Borne Encephalitis Virus Infections." Viruses 13, no. 4 (March 31, 2021): 596. http://dx.doi.org/10.3390/v13040596.
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Flaviviruses circulate worldwide and cause a number of medically relevant human diseases, such as dengue, Zika, yellow fever, and tick-borne encephalitis (TBE). Serology plays an important role in the diagnosis of flavivirus infections, but can be impeded by antigenic cross-reactivities among flaviviruses. Therefore, serological diagnosis of a recent infection can be insufficiently specific, especially in areas where flaviviruses co-circulate and/or vaccination coverage against certain flaviviruses is high. In this study, we developed a new IgM assay format, which is well suited for the specific diagnosis of TBE, Zika and dengue virus infections. In the case of TBE and Zika, the IgM response proved to be highly specific for the infecting virus. In contrast, primary dengue virus infections induced substantial amounts of cross-reactive IgM antibodies, which is most likely explained by structural peculiarities of dengue virus particles. Despite the presence of cross-reactive IgM, the standardized nature and the quantitative read-out of the assay even allowed the serotype-specific diagnosis of recent dengue virus infections in most instances.
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Samuel, Glady Hazitha, Michael R. Wiley, Atif Badawi, Zach N. Adelman, and Kevin M. Myles. "Yellow fever virus capsid protein is a potent suppressor of RNA silencing that binds double-stranded RNA." Proceedings of the National Academy of Sciences 113, no. 48 (November 14, 2016): 13863–68. http://dx.doi.org/10.1073/pnas.1600544113.
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Mosquito-borne flaviviruses, including yellow fever virus (YFV), Zika virus (ZIKV), and West Nile virus (WNV), profoundly affect human health. The successful transmission of these viruses to a human host depends on the pathogen’s ability to overcome a potentially sterilizing immune response in the vector mosquito. Similar to other invertebrate animals and plants, the mosquito’s RNA silencing pathway comprises its primary antiviral defense. Although a diverse range of plant and insect viruses has been found to encode suppressors of RNA silencing, the mechanisms by which flaviviruses antagonize antiviral small RNA pathways in disease vectors are unknown. Here we describe a viral suppressor of RNA silencing (VSR) encoded by the prototype flavivirus, YFV. We show that the YFV capsid (YFC) protein inhibits RNA silencing in the mosquitoAedes aegyptiby interfering with Dicer. This VSR activity appears to be broadly conserved in the C proteins of other medically important flaviviruses, including that of ZIKV. These results suggest that a molecular “arms race” between vector and pathogen underlies the continued existence of flaviviruses in nature.
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Hackett, Brent A., and Sara Cherry. "Flavivirus internalization is regulated by a size-dependent endocytic pathway." Proceedings of the National Academy of Sciences 115, no. 16 (April 2, 2018): 4246–51. http://dx.doi.org/10.1073/pnas.1720032115.
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Flaviviruses enter host cells through the process of clathrin-mediated endocytosis, and the spectrum of host factors required for this process are incompletely understood. Here we found that lymphocyte antigen 6 locus E (LY6E) promotes the internalization of multiple flaviviruses, including West Nile virus, Zika virus, and dengue virus. Perhaps surprisingly, LY6E is dispensable for the internalization of the endogenous cargo transferrin, which is also dependent on clathrin-mediated endocytosis for uptake. Since viruses are substantially larger than transferrin, we reasoned that LY6E may be required for uptake of larger cargoes and tested this using transferrin-coated beads of similar size as flaviviruses. LY6E was indeed required for the internalization of transferrin-coated beads, suggesting that LY6E is selectively required for large cargo. Cell biological studies found that LY6E forms tubules upon viral infection and bead internalization, and we found that tubule formation was dependent on RNASEK, which is also required for flavivirus internalization, but not transferrin uptake. Indeed, we found that RNASEK is also required for the internalization of transferrin-coated beads, suggesting it functions upstream of LY6E. These LY6E tubules resembled microtubules, and we found that microtubule assembly was required for their formation and flavivirus uptake. Since microtubule end-binding proteins link microtubules to downstream activities, we screened the three end-binding proteins and found that EB3 promotes virus uptake and LY6E tubularization. Taken together, these results highlight a specialized pathway required for the uptake of large clathrin-dependent endocytosis cargoes, including flaviviruses.
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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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Suzuki, Youichi, and Takeshi Murakawa. "Restriction of Flaviviruses by an Interferon-Stimulated Gene SHFL/C19orf66." International Journal of Molecular Sciences 23, no. 20 (October 20, 2022): 12619. http://dx.doi.org/10.3390/ijms232012619.
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Flaviviruses (the genus Flavivirus of the Flaviviridae family) include many arthropod-borne viruses, often causing life-threatening diseases in humans, such as hemorrhaging and encephalitis. Although the flaviviruses have a significant clinical impact, it has become apparent that flavivirus replication is restricted by cellular factors induced by the interferon (IFN) response, which are called IFN-stimulated genes (ISGs). SHFL (shiftless antiviral inhibitor of ribosomal frameshifting) is a novel ISG that inhibits dengue virus (DENV), West Nile virus (WNV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV) infections. Interestingly, SHFL functions as a broad-spectrum antiviral factor exhibiting suppressive activity against various types of RNA and DNA viruses. In this review, we summarize the current understanding of the molecular mechanisms by which SHFL inhibits flavivirus infection and discuss the molecular basis of the inhibitory mechanism using a predicted tertiary structure of SHFL generated by the program AlphaFold2.
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Biering, Scott B., David L. Akey, Marcus P. Wong, W. Clay Brown, Nicholas T. N. Lo, Henry Puerta-Guardo, Francielle Tramontini Gomes de Sousa, et al. "Structural basis for antibody inhibition of flavivirus NS1–triggered endothelial dysfunction." Science 371, no. 6525 (January 7, 2021): 194–200. http://dx.doi.org/10.1126/science.abc0476.
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Medically important flaviviruses cause diverse disease pathologies and collectively are responsible for a major global disease burden. A contributing factor to pathogenesis is secreted flavivirus nonstructural protein 1 (NS1). Despite demonstrated protection by NS1-specific antibodies against lethal flavivirus challenge, the structural and mechanistic basis remains unknown. Here, we present three crystal structures of full-length dengue virus NS1 complexed with a flavivirus–cross-reactive, NS1-specific monoclonal antibody, 2B7, at resolutions between 2.89 and 3.96 angstroms. These structures reveal a protective mechanism by which two domains of NS1 are antagonized simultaneously. The NS1 wing domain mediates cell binding, whereas the β-ladder triggers downstream events, both of which are required for dengue, Zika, and West Nile virus NS1–mediated endothelial dysfunction. These observations provide a mechanistic explanation for 2B7 protection against NS1-induced pathology and demonstrate the potential of one antibody to treat infections by multiple flaviviruses.