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1
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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Musso, Didier, and Philippe Desprès. "Serological Diagnosis of Flavivirus-Associated Human Infections." Diagnostics 10, no. 5 (May 14, 2020): 302. http://dx.doi.org/10.3390/diagnostics10050302.
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Arthropod-borne viruses (arboviruses) belonging to the Flavivirus genus of the Flaviviridae family, are a major public health threat in tropical and subtropical regions, and have recently become a medical concern in temperate zones. Most flaviviruses are classified as zoonotic viruses. Human flavivirus infections can be asymptomatic, responsible for unspecific symptoms in the first few days following infection, or responsible for severe complications potentially resulting in death. During the first days following symptom onset, laboratory diagnosis of acute human flavivirus infection is mainly based on molecular detection of the viral genome by RT-PCR methods, followed by the capture of specific antibodies using serological tests after the first week of infection. The detection of antibodies that have virus neutralizing activity can be used to confirm flavivirus infection. However, human flavivirus infections induce the production of cross-reactive antibodies, often making serology inconclusive. Indeed, serological diagnosis of flavivirus infection can be hampered by a patient’s history of flavivirus exposure, particularly in regions where multiple antigenically related flaviviruses co-circulate. We focus our mini review on conventional immunoassays that allow the diagnosis of major flavivirus-associated human infections in basic, routine and high-profile central health centers; and the interpretation of diagnostic serology tests for patients living within different epidemiological situations.
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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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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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Ke, Po-Yuan. "The Multifaceted Roles of Autophagy in Flavivirus-Host Interactions." International Journal of Molecular Sciences 19, no. 12 (December 7, 2018): 3940. http://dx.doi.org/10.3390/ijms19123940.
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Autophagy is an evolutionarily conserved cellular process in which intracellular components are eliminated via lysosomal degradation to supply nutrients for organelle biogenesis and metabolic homeostasis. Flavivirus infections underlie multiple human diseases and thus exert an immense burden on public health worldwide. Mounting evidence indicates that host autophagy is subverted to modulate the life cycles of flaviviruses, such as hepatitis C virus, dengue virus, Japanese encephalitis virus, West Nile virus and Zika virus. The diverse interplay between autophagy and flavivirus infection not only regulates viral growth in host cells but also counteracts host stress responses induced by viral infection. In this review, we summarize the current knowledge on the role of autophagy in the flavivirus life cycle. We also discuss the impacts of virus-induced autophagy on the pathogeneses of flavivirus-associated diseases and the potential use of autophagy as a therapeutic target for curing flavivirus infections and related human diseases.
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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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Ledermann, Jeremy P., Maria A. Lorono-Pino, Christine Ellis, Kali D. Saxton-Shaw, Bradley J. Blitvich, Barry J. Beaty, Richard A. Bowen, and Ann M. Powers. "Evaluation of Widely Used Diagnostic Tests To Detect West Nile Virus Infections in Horses Previously Infected with St. Louis Encephalitis Virus or Dengue Virus Type 2." Clinical and Vaccine Immunology 18, no. 4 (February 23, 2011): 580–87. http://dx.doi.org/10.1128/cvi.00201-10.
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ABSTRACTPrimary West Nile virus (WNV) infections can be diagnosed using a number of tests that detect infectious particles, nucleic acid, and specific IgM and/or IgG antibodies. However, serological identification of the infecting agent in secondary or subsequent flavivirus infections is problematic due to the extensive cross-reactivity of flavivirus antibodies. This is particularly difficult in the tropical Americas where multiple flaviviruses cocirculate. A study of sequential flavivirus infection in horses was undertaken using three medically important flaviviruses and five widely utilized diagnostic assays to determine if WNV infection in horses that had a previous St. Louis encephalitis virus (SLEV) or dengue virus type 2 (DENV-2) infection could be diagnosed. Following the primary inoculation, 25% (3/12) and 75% (3/4) of the horses mounted antibody responses against SLEV and DENV-2, respectively. Eighty-eight percent of horses subsequently inoculated with WNV had a WNV-specific antibody response that could be detected with one of these assays. The plaque reduction neutralization test (PRNT) was sensitive in detection but lacked specificity, especially following repeated flavivirus exposure. The WNV-specific IgM enzyme-linked immunosorbent assay (IgM ELISA) was able to detect an IgM antibody response and was not cross-reactive in a primary SLEV or DENV response. The WNV-specific blocking ELISA was specific, showing positives only following a WNV injection. Of great importance, we demonstrated that timing of sample collection and the need for multiple samples are important, as the infecting etiology could be misdiagnosed if only a single sample is tested.
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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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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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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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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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Reyes-Ruiz, José Manuel, Juan Fidel Osuna-Ramos, Luis Adrián De Jesús-González, Selvin Noé Palacios-Rápalo, Carlos Daniel Cordero-Rivera, Carlos Noe Farfan-Morales, Arianna Mahely Hurtado-Monzón, et al. "The Regulation of Flavivirus Infection by Hijacking Exosome-Mediated Cell–Cell Communication: New Insights on Virus–Host Interactions." Viruses 12, no. 7 (July 16, 2020): 765. http://dx.doi.org/10.3390/v12070765.
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The arthropod-borne flaviviruses are important human pathogens, and a deeper understanding of the virus–host cell interaction is required to identify cellular targets that can be used as therapeutic candidates. It is well reported that the flaviviruses hijack several cellular functions, such as exosome-mediated cell communication during infection, which is modulated by the delivery of the exosomal cargo of pro- or antiviral molecules to the receiving host cells. Therefore, to study the role of exosomes during flavivirus infections is essential, not only to understand its relevance in virus–host interaction, but also to identify molecular factors that may contribute to the development of new strategies to block these viral infections. This review explores the implications of exosomes in flavivirus dissemination and transmission from the vector to human host cells, as well as their involvement in the host immune response. The hypothesis about exosomes as a transplacental infection route of ZIKV and the paradox effect or the dual role of exosomes released during flavivirus infection are also discussed here. Although several studies have been performed in order to identify and characterize cellular and viral molecules released in exosomes, it is not clear how all of these components participate in viral pathogenesis. Further studies will determine the balance between protective and harmful exosomes secreted by flavivirus infected cells, the characteristics and components that distinguish them both, and how they could be a factor that determines the infection outcome.
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Pardy, Ryan D., and Martin J. Richer. "Protective to a T: The Role of T Cells during Zika Virus Infection." Cells 8, no. 8 (August 3, 2019): 820. http://dx.doi.org/10.3390/cells8080820.
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CD4 and CD8 T cells are an important part of the host’s capacity to defend itself against viral infections. During flavivirus infections, T cells have been implicated in both protective and pathogenic responses. Given the recent emergence of Zika virus (ZIKV) as a prominent global health threat, the question remains as to how T cells contribute to anti-ZIKV immunity. Furthermore, high homology between ZIKV and other, co-circulating flaviviruses opens the possibility of positive or negative effects of cross-reactivity due to pre-existing immunity. In this review, we will discuss the CD4 and CD8 T cell responses to ZIKV, and the lessons we have learned from both mouse and human infections. In addition, we will consider the possibility of whether T cells, in the context of flavivirus-naïve and flavivirus-immune subjects, play a role in promoting ZIKV pathogenesis during infection.
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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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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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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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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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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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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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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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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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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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Lee, Tae Hee, Byung-Hak Song, Sang-Im Yun, Hye Ryun Woo, Young-Min Lee, Michael S. Diamond, and Kyung Min Chung. "A cross-protective mAb recognizes a novel epitope within the flavivirus NS1 protein." Journal of General Virology 93, no. 1 (January 1, 2012): 20–26. http://dx.doi.org/10.1099/vir.0.036640-0.
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Despite a resurgence of flavivirus infections worldwide, no approved therapeutic agent exists for any member of the genus. While cross-reactive antibodies with therapeutic potential against flaviviruses have been generated, the majority of them are anti-E antibodies with the potential to cause antibody-dependent enhancement of flavivirus infection and disease. We described previously mAbs against the non-structural NS1 protein of the West Nile virus (WNV) that were protective in mice when administered pre- or post-infection of WNV. Here, we demonstrate that one of these mAbs (16NS1) cross-reacted with Japanese encephalitis virus (JEV) and exhibited protective activity against a lethal JEV infection. Overlapping peptide mapping analysis combined with site-specific mutations identified a novel epitope 116KAWGKSILFA125 and critical amino acid residues (118W and 122I) for 16NS1 mAb binding. These results may facilitate the development of a broadly therapeutic mAb that lacks enhancing potential and/or subunit-based vaccine against flaviviruses that target the NS1 protein.
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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.
Full textAbstract:
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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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.
Full textAbstract:
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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Chiou, Shyan-Song, Wayne D. Crill, Li-Kuang Chen, and Gwong-Jen J. Chang. "Enzyme-Linked Immunosorbent Assays Using Novel Japanese Encephalitis Virus Antigen Improve the Accuracy of Clinical Diagnosis of Flavivirus Infections." Clinical and Vaccine Immunology 15, no. 5 (March 12, 2008): 825–35. http://dx.doi.org/10.1128/cvi.00004-08.
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ABSTRACT The cross-reactive antibodies induced by flavivirus infections confound serodiagnosis and pathogenesis, especially in secondary infections caused by antigenically closely related yet distinct flaviviruses. The envelope (E) glycoprotein fusion peptide contains immunodominant cross-reactive determinants. Using a recombinant Japanese encephalitis virus (JEV) premembrane and E expression plasmid producing JEV virus-like particles (VLPs), dramatic reductions in cross-reactivity were produced by the G106K-L107D (KD) double-mutant VLP against a panel of flavivirus murine monoclonal antibodies. Human serum panels from patients with recent flavivirus infections were analyzed to compare the accuracy of JEV wild-type (WT) and KD VLPs as serodiagnostic antigens in enzyme-linked immunosorbent assays. Statistical analysis demonstrated significant differences in assay performances for accurate determination of current JEV infections between WT and KD antigens by detecting immunoglobulin M antibodies at a serum dilution of 1:4,000 (likelihood ratios = 2.74 [WT] and 22 [KD]). The application and continued development of cross-reactivity-reduced antigens should improve both flavivirus infection serodiagnosis and estimates of disease burden.
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Whelan, Jillian N., Nicholas A. Parenti, Joshua Hatterschide, David M. Renner, Yize Li, Hanako M. Reyes, Beihua Dong, Erick R. Perez, Robert H. Silverman, and Susan R. Weiss. "Zika virus employs the host antiviral RNase L protein to support replication factory assembly." Proceedings of the National Academy of Sciences 118, no. 22 (May 24, 2021): e2101713118. http://dx.doi.org/10.1073/pnas.2101713118.
Full textAbstract:
Infection with the flavivirus Zika virus (ZIKV) can result in tissue tropism, disease outcome, and route of transmission distinct from those of other flaviviruses; therefore, we aimed to identify host machinery that exclusively promotes the ZIKV replication cycle, which can inform on differences at the organismal level. We previously reported that deletion of the host antiviral ribonuclease L (RNase L) protein decreases ZIKV production. Canonical RNase L catalytic activity typically restricts viral infection, including that of the flavivirus dengue virus (DENV), suggesting an unconventional, proviral RNase L function during ZIKV infection. In this study, we reveal that an inactive form of RNase L supports assembly of ZIKV replication factories (RFs) to enhance infectious virus production. Compared with the densely concentrated ZIKV RFs generated with RNase L present, deletion of RNase L induced broader subcellular distribution of ZIKV replication intermediate double-stranded RNA (dsRNA) and NS3 protease, two constituents of ZIKV RFs. An inactive form of RNase L was sufficient to contain ZIKV genome and dsRNA within a smaller RF area, which subsequently increased infectious ZIKV release from the cell. Inactive RNase L can interact with cytoskeleton, and flaviviruses remodel cytoskeleton to construct RFs. Thus, we used the microtubule-stabilization drug paclitaxel to demonstrate that ZIKV repurposes RNase L to facilitate the cytoskeleton rearrangements required for proper generation of RFs. During infection with flaviviruses DENV or West Nile Kunjin virus, inactive RNase L did not improve virus production, suggesting that a proviral RNase L role is not a general feature of all flavivirus infections.
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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.
Full textAbstract:
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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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.
Full textAbstract:
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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Göertz, G. P., J. J. Fros, P. Miesen, C. B. F. Vogels, M. L. van der Bent, C. Geertsema, C. J. M. Koenraadt, R. P. van Rij, M. M. van Oers, and G. P. Pijlman. "Noncoding Subgenomic Flavivirus RNA Is Processed by the Mosquito RNA Interference Machinery and Determines West Nile Virus Transmission by Culex pipiens Mosquitoes." Journal of Virology 90, no. 22 (August 31, 2016): 10145–59. http://dx.doi.org/10.1128/jvi.00930-16.
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ABSTRACT Flaviviruses, such as Zika virus, yellow fever virus, dengue virus, and West Nile virus (WNV), are a serious concern for human health. Flaviviruses produce an abundant noncoding subgenomic flavivirus RNA (sfRNA) in infected cells. sfRNA results from stalling of the host 5′-3′ exoribonuclease XRN1/Pacman on conserved RNA structures in the 3′ untranslated region (UTR) of the viral genomic RNA. sfRNA production is conserved in insect-specific, mosquito-borne, and tick-borne flaviviruses and flaviviruses with no known vector, suggesting a pivotal role for sfRNA in the flavivirus life cycle. Here, we investigated the function of sfRNA during WNV infection of Culex pipiens mosquitoes and evaluated its role in determining vector competence. An sfRNA1-deficient WNV was generated that displayed growth kinetics similar to those of wild-type WNV in both RNA interference (RNAi)-competent and -compromised mosquito cell lines. Small-RNA deep sequencing of WNV-infected mosquitoes indicated an active small interfering RNA (siRNA)-based antiviral response for both the wild-type and sfRNA1-deficient viruses. Additionally, we provide the first evidence that sfRNA is an RNAi substrate in vivo . Two reproducible small-RNA hot spots within the 3′ UTR/sfRNA of the wild-type virus mapped to RNA stem-loops SL-III and 3′ SL, which stick out of the three-dimensional (3D) sfRNA structure model. Importantly, we demonstrate that sfRNA-deficient WNV displays significantly decreased infection and transmission rates in vivo when administered via the blood meal. Finally, we show that transmission and infection rates are not affected by sfRNA after intrathoracic injection, thereby identifying sfRNA as a key driver to overcome the mosquito midgut infection barrier. This is the first report to describe a key biological function of sfRNA for flavivirus infection of the arthropod vector, providing an explanation for the strict conservation of sfRNA production. IMPORTANCE Understanding the flavivirus transmission cycle is important to identify novel targets to interfere with disease and to aid development of virus control strategies. Flaviviruses produce an abundant noncoding viral RNA called sfRNA in both arthropod and mammalian cells. To evaluate the role of sfRNA in flavivirus transmission, we infected mosquitoes with the flavivirus West Nile virus and an sfRNA-deficient mutant West Nile virus. We demonstrate that sfRNA determines the infection and transmission rates of West Nile virus in Culex pipiens mosquitoes. Comparison of infection via the blood meal versus intrathoracic injection, which bypasses the midgut, revealed that sfRNA is important to overcome the mosquito midgut barrier. We also show that sfRNA is processed by the antiviral RNA interference machinery in mosquitoes. This is the first report to describe a pivotal biological function of sfRNA in arthropods. The results explain why sfRNA production is evolutionarily conserved.
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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.
Full textAbstract:
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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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.
Full textAbstract:
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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Torres, Francisco J., Rhys Parry, Leon E. Hugo, Andrii Slonchak, Natalee D. Newton, Laura J. Vet, Naphak Modhiran, et al. "Reporter Flaviviruses as Tools to Demonstrate Homologous and Heterologous Superinfection Exclusion." Viruses 14, no. 7 (July 8, 2022): 1501. http://dx.doi.org/10.3390/v14071501.
Full textAbstract:
Binjari virus (BinJV) is a lineage II or dual-host affiliated insect-specific flavivirus previously demonstrated as replication-deficient in vertebrate cells. Previous studies have shown that BinJV is tolerant to exchanging its structural proteins (prM-E) with pathogenic flaviviruses, making it a safe backbone for flavivirus vaccines. Here, we report generation by circular polymerase extension reaction of BinJV expressing zsGreen or mCherry fluorescent protein. Recovered BinJV reporter viruses grew to high titres (107−8 FFU/mL) in Aedes albopictus C6/36 cells assayed using immunoplaque assays (iPA). We also demonstrate that BinJV reporters could be semi-quantified live in vitro using a fluorescence microplate reader with an observed linear correlation between quantified fluorescence of BinJV reporter virus-infected C6/36 cells and iPA-quantitated virus titres. The utility of the BinJV reporter viruses was then examined in homologous and heterologous superinfection exclusion assays. We demonstrate that primary infection of C6/36 cells with BinJVzsGreen completely inhibits a secondary infection with homologous BinJVmCherry or heterologous ZIKVmCherry using fluorescence microscopy and virus quantitation by iPA. Finally, BinJVzsGreen infections were examined in vivo by microinjection of Aedes aegypti with BinJVzsGreen. At seven days post-infection, a strong fluorescence in the vicinity of salivary glands was detected in frozen sections. This is the first report on the construction of reporter viruses for lineage II insect-specific flaviviruses and establishes a tractable system for exploring flavivirus superinfection exclusion in vitro and in vivo.
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Balingit, Jean Claude, Minh Huong Phu Ly, Mami Matsuda, Ryosuke Suzuki, Futoshi Hasebe, Kouichi Morita, and Meng Ling Moi. "A Simple and High-Throughput ELISA-Based Neutralization Assay for the Determination of Anti-Flavivirus Neutralizing Antibodies." Vaccines 8, no. 2 (June 10, 2020): 297. http://dx.doi.org/10.3390/vaccines8020297.
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Mosquito-borne flavivirus infections, including dengue virus and Zika virus, are major public health threats globally. While the plaque reduction neutralization test (PRNT) is considered the gold standard for determining neutralizing antibody levels to flaviviruses, the assay is time-consuming and laborious. This study, therefore, aimed to develop an enzyme-linked immunosorbent assay (ELISA)-based microneutralization test (EMNT) for the detection of neutralizing antibodies to mosquito-borne flaviviruses. The inhibition of viral growth due to neutralizing antibodies was determined colorimetrically by using EMNT. Given the significance of Fcγ-receptors (FcγR) in antibody-mediated neutralization and antibody-dependent enhancement (ADE) of flavivirus infection, non-FcγR and FcγR-expressing cell lines were used in the EMNT to allow the detection of the sum of neutralizing and immune-enhancing antibody activity as the neutralizing titer. Using anti-flavivirus monoclonal antibodies and clinical samples, the utility of EMNT was evaluated by comparing the end-point titers of the EMNT and the PRNT. The correlation between EMNT and PRNT titers was strong, indicating that EMNT was robust and reproducible. The new EMNT assay combines the biological functional assessment of virus neutralization activity and the technical advantages of ELISA and, is simple, reliable, practical, and could be automated for high-throughput implementation in flavivirus surveillance studies and vaccine trials.
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Hassert, Mariah, James D. Brien, and Amelia K. Pinto. "T cell cross-reactivity during heterologous infection results in immunodomination and enhanced cytolytic capacity at the expense of virus-specific responses." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 103.27. http://dx.doi.org/10.4049/jimmunol.206.supp.103.27.
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Abstract Flaviviruses constitute a genus of closely related arthropod-borne viruses including Zika virus, the four serotypes of dengue virus, and yellow fever virus, which circulate in the same geographic regions. These viruses share a substantial degree of genetic similarity and consequently, antigenic overlap has been reported by evaluating T cell and antibody responses in humans, non-human primates, and mice. However, it has not been determined how existing immunity to a heterologous flavivirus impacts functional immune responses to virus-specific and cross-reactive epitopes. We hypothesize that cross-reactive T cells from prior flavivirus exposures will expand robustly during a heterologous challenge and that these cells primed during a heterologous infection will be functionally different from cells of the same specificity primed during a homologous infection. Using various mouse models of flavivirus infection, we have identified a pan-flavivirus reactive CD8+ T cell epitope. We show in a heterologous infection model in which dengue virus exposure precedes Zika virus infection, T cell responses to the cross-reactive epitope dominate at the expense of the Zika-specific T cell responses. These cross-reactive T cells display enhanced killing capacity, in addition to other functional changes. The culmination of these features drive altered protective capacity when compared to homologously primed T cells in our mouse model of Zika infection. Our findings provide a mechanistic understanding of cross-reactive T cell control during heterologous infection and have important implications for vaccine design, as these results define the functional consequences of priming a cross-reactive T cell response for a pan-flavivirus vaccine.
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Hassert, Mariah, James D. Brien, and Amelia K. Pinto. "CD8+ T cell cross-reactivity during heterologous flavivirus infection results in cross-reactive immunodomination and enhanced cytolytic capacity at the expense of virus-specific responses." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 95.9. http://dx.doi.org/10.4049/jimmunol.204.supp.95.9.
Full textAbstract:
Abstract Flaviviruses constitute a genus of closely related arthropod-borne viruses including Zika virus, the four serotypes of dengue virus, and yellow fever virus, which circulate in the same geographic regions. These viruses share a substantial degree of genetic similarity and consequently, antigenic overlap has been reported by evaluating T cell and antibody responses in humans, non-human primates, and mice. However, it has not been determined how existing immunity to a heterologous flavivirus impacts functional immune responses to virus-specific and cross-reactive epitopes. We hypothesize that cross-reactive T cells from prior flavivirus exposures will expand robustly during a heterologous challenge and that these cells primed during a heterologous infection will be functionally different from cells of the same specificity primed during a homologous infection. Using various mouse models of flavivirus infection, we have identified a pan-flavivirus reactive CD8+ T cell epitope. We show in a heterologous infection model in which dengue virus exposure precedes Zika virus infection, T cell responses to the cross-reactive epitope dominate at the expense of the Zika-specific T cell responses. These cross-reactive T cells display enhanced killing capacity, in addition to other functional changes. The culmination of these features drive altered protective capacity when compared to homologously primed T cells in our mouse model of Zika infection. Our findings provide a mechanistic understanding of cross-reactive T cell control during heterologous infection and have important implications for vaccine design, as these results define the functional consequences of priming a cross-reactive T cell response for a pan-flavivirus vaccine.
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You, Jaehwan, Shangmei Hou, Natasha Malik-Soni, Zaikun Xu, Anil Kumar, Richard A. Rachubinski, Lori Frappier, and Tom C. Hobman. "Flavivirus Infection Impairs Peroxisome Biogenesis and Early Antiviral Signaling." Journal of Virology 89, no. 24 (September 30, 2015): 12349–61. http://dx.doi.org/10.1128/jvi.01365-15.
Full textAbstract:
ABSTRACTFlaviviruses are significant human pathogens that have an enormous impact on the global health burden. Currently, there are very few vaccines against or therapeutic treatments for flaviviruses, and our understanding of how these viruses cause disease is limited. Evidence suggests that the capsid proteins of flaviviruses play critical nonstructural roles during infection, and therefore, elucidating how these viral proteins affect cellular signaling pathways could lead to novel targets for antiviral therapy. We used affinity purification to identify host cell proteins that interact with the capsid proteins of West Nile and dengue viruses. One of the cellular proteins that formed a stable complex with flavivirus capsid proteins is the peroxisome biogenesis factor Pex19. Intriguingly, flavivirus infection resulted in a significant loss of peroxisomes, an effect that may be due in part to capsid expression. We posited that capsid protein-mediated sequestration and/or degradation of Pex19 results in loss of peroxisomes, a situation that could result in reduced early antiviral signaling. In support of this hypothesis, we observed that induction of the lambda interferon mRNA in response to a viral RNA mimic was reduced by more than 80%. Together, our findings indicate that inhibition of peroxisome biogenesis may be a novel mechanism by which flaviviruses evade the innate immune system during early stages of infection.IMPORTANCERNA viruses infect hundreds of millions of people each year, causing significant morbidity and mortality. Chief among these pathogens are the flaviviruses, which include dengue virus and West Nile virus. Despite their medical importance, there are very few prophylactic or therapeutic treatments for these viruses. Moreover, the manner in which they subvert the innate immune response in order to establish infection in mammalian cells is not well understood. Recently, peroxisomes were reported to function in early antiviral signaling, but very little is known regarding if or how pathogenic viruses affect these organelles. We report for the first time that flavivirus infection results in significant loss of peroxisomes in mammalian cells, which may indicate that targeting of peroxisomes is a key strategy used by viruses to subvert early antiviral defenses.
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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.
Full textAbstract:
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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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.
Full textAbstract:
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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Merino-Ramos, Teresa, Ángela Vázquez-Calvo, Josefina Casas, Francisco Sobrino, Juan-Carlos Saiz, and Miguel A. Martín-Acebes. "Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication." Antimicrobial Agents and Chemotherapy 60, no. 1 (October 26, 2015): 307–15. http://dx.doi.org/10.1128/aac.01578-15.
Full textAbstract:
ABSTRACTWest Nile virus (WNV) is a neurotropic flavivirus transmitted by the bite of mosquitoes that causes meningitis and encephalitis in humans, horses, and birds. Several studies have highlighted that flavivirus infection is highly dependent on cellular lipids for virus replication and infectious particle biogenesis. The first steps of lipid synthesis involve the carboxylation of acetyl coenzyme A (acetyl-CoA) to malonyl-CoA that is catalyzed by the acetyl-CoA carboxylase (ACC). This makes ACC a key enzyme of lipid synthesis that is currently being evaluated as a therapeutic target for different disorders, including cancers, obesity, diabetes, and viral infections. We have analyzed the effect of the ACC inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) on infection by WNV. Lipidomic analysis of TOFA-treated cells confirmed that this drug reduced the cellular content of multiple lipids, including those directly implicated in the flavivirus life cycle (glycerophospholipids, sphingolipids, and cholesterol). Treatment with TOFA significantly inhibited the multiplication of WNV in a dose-dependent manner. Further analysis of the antiviral effect of this drug showed that the inhibitory effect was related to a reduction of viral replication. Furthermore, treatment with another ACC inhibitor, 3,3,14,14-tetramethylhexadecanedioic acid (MEDICA 16), also inhibited WNV infection. Interestingly, TOFA and MEDICA 16 also reduced the multiplication of Usutu virus (USUV), a WNV-related flavivirus. These results point to the ACC as a druggable cellular target suitable for antiviral development against WNV and other flaviviruses.
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Momburg, Frank, Arno Müllbacher, and Mario Lobigs. "Modulation of Transporter Associated with Antigen Processing (TAP)-Mediated Peptide Import into the Endoplasmic Reticulum by Flavivirus Infection." Journal of Virology 75, no. 12 (June 15, 2001): 5663–71. http://dx.doi.org/10.1128/jvi.75.12.5663-5671.2001.
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ABSTRACT In contrast to many other viruses that escape the cellular immune response by downregulating major histocompatibility complex (MHC) class I molecules, flavivirus infection can upregulate their cell surface expression. Previously we have presented evidence that during flavivirus infection, peptide supply to the endoplasmic reticulum is increased (A. Müllbacher and M. Lobigs, Immunity 3:207–214, 1995). Here we show that during the early phase of infection with different flaviviruses, the transport activity of the peptide transporter associated with antigen processing (TAP) is augmented by up to 50%. TAP expression is unaltered during infection, and viral but not host macromolecular synthesis is required for enhanced peptide transport. This study is the first demonstration of transient enhancement of TAP-dependent peptide import into the lumen of the endoplasmic reticulum as a consequence of a viral infection. We suggest that the increased supply of peptides for assembly with MHC class I molecules in flavivirus-infected cells accounts for the upregulation of MHC class I cell surface expression with the biological consequence of viral evasion of natural killer cell recognition.
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Arias-Arias, Jorge L., Derek J. MacPherson, Maureen E. Hill, Jeanne A. Hardy, and Rodrigo Mora-Rodríguez. "A fluorescence-activatable reporter of flavivirus NS2B–NS3 protease activity enables live imaging of infection in single cells and viral plaques." Journal of Biological Chemistry 295, no. 8 (January 9, 2020): 2212–26. http://dx.doi.org/10.1074/jbc.ra119.011319.
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The genus Flavivirus in the family Flaviviridae comprises many medically important viruses, such as dengue virus (DENV), Zika virus (ZIKV), and yellow fever virus. The quest for therapeutic targets to combat flavivirus infections requires a better understanding of the kinetics of virus–host interactions during infections with native viral strains. However, this is precluded by limitations of current cell-based systems for monitoring flavivirus infection in living cells. In the present study, we report the construction of fluorescence-activatable sensors to detect the activities of flavivirus NS2B–NS3 serine proteases in living cells. The system consists of GFP-based reporters that become fluorescent upon cleavage by recombinant DENV-2/ZIKV proteases in vitro. A version of this sensor containing the flavivirus internal NS3 cleavage site linker reported the highest fluorescence activation in stably transduced mammalian cells upon DENV-2/ZIKV infection. Moreover, the onset of fluorescence correlated with viral protease activity. A far-red version of this flavivirus sensor had the best signal-to-noise ratio in a fluorescent Dulbecco's plaque assay, leading to the construction of a multireporter platform combining the flavivirus sensor with reporter dyes for detection of chromatin condensation and cell death, enabling studies of viral plaque formation with single-cell resolution. Finally, the application of this platform enabled the study of cell-population kinetics of infection and cell death by DENV-2, ZIKV, and yellow fever virus. We anticipate that future studies of viral infection kinetics with this reporter system will enable basic investigations of virus–host interactions and facilitate future applications in antiviral drug research to manage flavivirus infections.
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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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Evangelista, Julio, Cristhopher Cruz, Carolina Guevara, Helvio Astete, Cristiam Carey, Tadeusz J. Kochel, Amy C. Morrison, Maya Williams, Eric S. Halsey, and Brett M. Forshey. "Characterization of a novel flavivirus isolated from Culex (Melanoconion) ocossa mosquitoes from Iquitos, Peru." Journal of General Virology 94, no. 6 (June 1, 2013): 1266–72. http://dx.doi.org/10.1099/vir.0.050575-0.
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We describe the isolation and characterization of a novel flavivirus, isolated from a pool of Culex (Melanoconion) ocossa Dyar and Knab mosquitoes collected in 2009 in an urban area of the Amazon basin city of Iquitos, Peru. Flavivirus infection was detected by indirect immunofluorescent assay of inoculated C6/36 cells using polyclonal flavivirus antibodies (St. Louis encephalitis virus, yellow fever virus and dengue virus type 1) and confirmed by RT-PCR. Based on partial sequencing of the E and NS5 gene regions, the virus isolate was most closely related to the mosquito-borne flaviviruses but divergent from known species, with less than 45 and 71 % pairwise amino acid identity in the E and NS5 gene products, respectively. Phylogenetic analysis of E and NS5 amino acid sequences demonstrated that this flavivirus grouped with mosquito-borne flaviviruses, forming a clade with Nounané virus (NOUV). Like NOUV, no replication was detected in a variety of mammalian cells (Vero-76, Vero-E6, BHK, LLCMK, MDCK, A549 and RD) or in intracerebrally inoculated newborn mice. We tentatively designate this genetically distinct flavivirus as representing a novel species, Nanay virus, after the river near where it was first detected.
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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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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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Charlier, Nathalie, Pieter Leyssen, Jan Paeshuyse, Christian Drosten, Herbert Schmitz, Alfons Van Lommel, Erik De Clercq, and Johan Neyts. "Infection of SCID mice with Montana Myotis leukoencephalitis virus as a model for flavivirus encephalitis." Journal of General Virology 83, no. 8 (August 1, 2002): 1887–96. http://dx.doi.org/10.1099/0022-1317-83-8-1887.
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We have established a convenient animal model for flavivirus encephalitis using Montana Myotis leukoencephalitis virus (MMLV), a bat flavivirus. This virus has the same genomic organization, and contains the same conserved motifs in genes that encode potential antiviral targets, as flaviviruses that cause disease in man (N. Charlier et al., accompanying paper), and has a similar particle size (approximately 40 nm). MMLV replicates well in Vero cells and appears to be equally as sensitive as yellow fever virus and dengue fever virus to a selection of experimental antiviral agents. Cells infected with MMLV show dilation of the endoplasmic reticulum, a characteristic of flavivirus infection. Intraperitoneal, intranasal or direct intracerebral inoculation of SCID mice with MMLV resulted in encephalitis ultimately leading to death, whereas immunocompetent mice were refractory to either intranasal or intraperitoneal infection with MMLV. Viral RNA and/or antigens were detected in the brain and serum of MMLV-infected SCID mice, but not in any other organ examined: MMLV was detected in the olfactory lobes, the cerebral cortex, the limbic structures, the midbrain, cerebellum and medulla oblongata. Infection was confined to neurons. Treatment with the interferon-α/β inducer poly(I)·poly(C) protected SCID mice against MMLV-induced morbidity and mortality, and this protection correlated with a reduction in infectious virus titre and viral RNA load. This validates the MMLV model for use in antiviral drug studies. The MMLV SCID model may, therefore, be attractive for the study of chemoprophylactic or chemotherapeutic strategies against flavivirus infections causing encephalitis.
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Wan, Shengfeng, Shengbo Cao, Xugang Wang, Yanfei Zhou, Weidong Yan, Xinbin Gu, Tzyy-Choou Wu, and Xiaowu Pang. "Evaluation of Vertebrate-Specific Replication-Defective Zika Virus, a Novel Single-Cycle Arbovirus Vaccine, in a Mouse Model." Vaccines 9, no. 4 (April 1, 2021): 338. http://dx.doi.org/10.3390/vaccines9040338.
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The flavivirus Zika (ZIKV) has emerged as a global threat, making the development of a ZIKV vaccine a priority. While live-attenuated vaccines are known to induce long-term immunity but reduced safety, inactivated vaccines exhibit a weaker immune response as a trade-off for increased safety margins. To overcome the trade-off between immunogenicity and safety, the concept of a third-generation flavivirus vaccine based on single-cycle flaviviruses has been developed. These third-generation flavivirus vaccines have demonstrated extreme potency with a high level of safety in animal models. However, the production of these single-cycle, encapsidation-defective flaviviruses requires a complicated virion packaging system. Here, we investigated a new single-cycle flavivirus vaccine, a vertebrate-specific replication-defective ZIKV (VSRD-ZIKV), in a mouse model. VSRD-ZIKV replicates to high titers in insect cells but can only initiate a single-round infection in vertebrate cells. During a single round of infection, VSRD-ZIKV can express all the authentic viral antigens in vertebrate hosts. VSRD-ZIKV immunization elicited a robust cellular and humoral immune response that protected against a lethal ZIKV challenge in AG129 mice. Additionally, VSRD-ZIKV-immunized pregnant mice were protected against vertically transferring a lethal ZIKV infection to their offspring. Immunized male mice were protected and prevented viral accumulation in the testes after being challenged with lethal ZIKV. Overall, our results indicate that VSRD-ZIKV induces a potent protective immunity against ZIKV in a mouse model and represents a promising approach to develop novel single-cycle arbovirus vaccines.
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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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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.