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Virulence Dec 2021The Flavivirus genus consists of >70 members including several that are considered significant human pathogens. Flaviviruses display a broad spectrum of diseases that... (Review)
Review
The Flavivirus genus consists of >70 members including several that are considered significant human pathogens. Flaviviruses display a broad spectrum of diseases that can be roughly categorised into two phenotypes - systemic disease involving haemorrhage exemplified by dengue and yellow Fever virus, and neurological complications associated with the likes of West Nile and Zika viruses. Attempts to develop vaccines have been variably successful against some. Besides, mosquito-borne flaviviruses can be vertically transmitted in the arthropods, enabling long term persistence and the possibility of re-emergence. Therefore, developing strategies to combat disease is imperative even if vaccines become available. The cellular interactions of flaviviruses with their human hosts are key to establishing the viral lifecycle on the one hand, and activation of host immunity on the other. The latter should ideally eradicate infection, but often leads to immunopathological and neurological consequences. In this review, we use Dengue and Zika viruses to discuss what we have learned about the cellular and molecular determinants of the viral lifecycle and the accompanying immunopathology, while highlighting current knowledge gaps which need to be addressed in future studies.
Topics: Animals; Dengue; Dengue Virus; Flavivirus; Flavivirus Infections; Virulence; Zika Virus; Zika Virus Infection
PubMed: 34696709
DOI: 10.1080/21505594.2021.1996059 -
Nature Microbiology Jun 2020Flaviviruses are vector-borne RNA viruses that can emerge unexpectedly in human populations and cause a spectrum of potentially severe diseases including hepatitis,... (Review)
Review
Flaviviruses are vector-borne RNA viruses that can emerge unexpectedly in human populations and cause a spectrum of potentially severe diseases including hepatitis, vascular shock syndrome, encephalitis, acute flaccid paralysis, congenital abnormalities and fetal death. This epidemiological pattern has occurred numerous times during the last 70 years, including epidemics of dengue virus and West Nile virus, and the most recent explosive epidemic of Zika virus in the Americas. Flaviviruses are now globally distributed and infect up to 400 million people annually. Of significant concern, outbreaks of other less well-characterized flaviviruses have been reported in humans and animals in different regions of the world. The potential for these viruses to sustain epidemic transmission among humans is poorly understood. In this Review, we discuss the basic biology of flaviviruses, their infectious cycles, the diseases they cause and underlying host immune responses to infection. We describe flaviviruses that represent an established ongoing threat to global health and those that have recently emerged in new populations to cause significant disease. We also provide examples of lesser-known flaviviruses that circulate in restricted areas of the world but have the potential to emerge more broadly in human populations. Finally, we discuss how an understanding of the epidemiology, biology, structure and immunity of flaviviruses can inform the rapid development of countermeasures to treat or prevent human infections as they emerge.
Topics: Animals; Communicable Diseases, Emerging; Female; Flavivirus; Flavivirus Infections; Geography, Medical; Global Health; Host-Pathogen Interactions; Humans; Pregnancy; T-Lymphocytes; Virion; Virus Replication
PubMed: 32367055
DOI: 10.1038/s41564-020-0714-0 -
The Journal of Infectious Diseases Dec 2017The emergence of Zika virus (ZIKV) as a major public health threat has focused research on understanding virus biology and developing a suite of strategies for disease... (Review)
Review
The emergence of Zika virus (ZIKV) as a major public health threat has focused research on understanding virus biology and developing a suite of strategies for disease intervention. Recent advances in cryoelectron microscopy have accelerated structure-function studies of flaviviruses and of ZIKV in particular. Structures of the mature and immature ZIKV have demonstrated its similarity with other known flaviviruses such as dengue and West Nile viruses. However, ZIKV's unique pathobiology demands an explanation of how its structure, although similar to its flavivirus relatives, is sufficiently unique to address questions of receptor specificity, transmission, and antigenicity. Progress in defining the immunodominant epitopes and how neutralizing antibodies bind to them will provide great insight as vaccines progress through clinical trials. Identification of host receptors will substantially illuminate the interesting ZIKV tropism and provide insights into pathogenesis. Although the answers to all of these questions are not yet available, rapid progress in combining structural biology with other techniques is revealing the similarities and the differences in virion structure and function between ZIKV and related flaviviruses.
Topics: Antibodies, Neutralizing; Antibodies, Viral; Cryoelectron Microscopy; Epitopes; Flavivirus; Humans; Immunogenicity, Vaccine; Virion; Zika Virus; Zika Virus Infection
PubMed: 29267925
DOI: 10.1093/infdis/jix515 -
Antiviral Research May 2013The flavivirus nonstructural glycoprotein NS1 is an enigmatic protein whose structure and mechanistic function have remained somewhat elusive ever since it was first... (Review)
Review
The flavivirus nonstructural glycoprotein NS1 is an enigmatic protein whose structure and mechanistic function have remained somewhat elusive ever since it was first reported in 1970 as a viral antigen circulating in the sera of dengue-infected patients. All flavivirus NS1 genes share a high degree of homology, encoding a 352-amino-acid polypeptide that has a molecular weight of 46-55 kDa, depending on its glycosylation status. NS1 exists in multiple oligomeric forms and is found in different cellular locations: a cell membrane-bound form in association with virus-induced intracellular vesicular compartments, on the cell surface and as a soluble secreted hexameric lipoparticle. Intracellular NS1 co-localizes with dsRNA and other components of the viral replication complex and plays an essential cofactor role in replication. Although this makes NS1 an ideal target for inhibitor design, the precise nature of its cofactor function has yet to be elucidated. A plethora of potential interacting partners have been identified, particularly for the secreted form of NS1, with many being implicated in immune evasion strategies. Secreted and cell-surface-associated NS1 are highly immunogenic and both the proteins themselves and the antibodies they elicit have been implicated in the seemingly contradictory roles of protection and pathogenesis in the infected host. Finally, NS1 is also an important biomarker for early diagnosis of disease. In this article, we provide an overview of these somewhat disparate areas of research, drawing together the wealth of data generated over more than 40 years of study of this fascinating protein.
Topics: Animals; Biomarkers; Flavivirus; Flavivirus Infections; Humans; Viral Nonstructural Proteins
PubMed: 23523765
DOI: 10.1016/j.antiviral.2013.03.008 -
Flavivirus NS1 Triggers Tissue-Specific Vascular Endothelial Dysfunction Reflecting Disease Tropism.Cell Reports Feb 2019Flaviviruses cause systemic or neurotropic-encephalitic pathology in humans. The flavivirus nonstructural protein 1 (NS1) is a secreted glycoprotein involved in viral...
Flaviviruses cause systemic or neurotropic-encephalitic pathology in humans. The flavivirus nonstructural protein 1 (NS1) is a secreted glycoprotein involved in viral replication, immune evasion, and vascular leakage during dengue virus infection. However, the contribution of secreted NS1 from related flaviviruses to viral pathogenesis remains unknown. Here, we demonstrate that NS1 from dengue, Zika, West Nile, Japanese encephalitis, and yellow fever viruses selectively binds to and alters permeability of human endothelial cells from lung, dermis, umbilical vein, brain, and liver in vitro and causes tissue-specific vascular leakage in mice, reflecting the pathophysiology of each flavivirus. Mechanistically, each flavivirus NS1 leads to differential disruption of endothelial glycocalyx components, resulting in endothelial hyperpermeability. Our findings reveal the capacity of a secreted viral protein to modulate endothelial barrier function in a tissue-specific manner both in vitro and in vivo, potentially influencing virus dissemination and pathogenesis and providing targets for antiviral therapies and vaccine development.
Topics: Animals; Brain; Cell Line; Cell Membrane Permeability; Dengue; Dengue Virus; Dermis; Encephalitis Virus, Japanese; Endothelial Cells; Gene Expression; Glycocalyx; Humans; Liver; Lung; Male; Mice; Organ Specificity; Primary Cell Culture; Umbilical Veins; Viral Nonstructural Proteins; Virus Replication; West Nile virus; Yellow fever virus; Zika Virus
PubMed: 30726741
DOI: 10.1016/j.celrep.2019.01.036 -
Journal of Virology Sep 2022Flaviviruses are positive-sense single-stranded RNA viruses, including some well-known human pathogens such as Zika, dengue, and yellow fever viruses, which are... (Review)
Review
Flaviviruses are positive-sense single-stranded RNA viruses, including some well-known human pathogens such as Zika, dengue, and yellow fever viruses, which are primarily associated with mosquito and tick vectors. The vast majority of flavivirus research has focused on terrestrial environments; however, recent findings indicate that a range of flaviviruses are also present in aquatic environments, both marine and freshwater. These flaviviruses are found in various hosts, including fish, crustaceans, molluscs, and echinoderms. Although the effects of aquatic flaviviruses on the hosts they infect are not all known, some have been detected in farmed species and may have detrimental effects on the aquaculture industry. Exploration of the evolutionary history through the discovery of the Wenzhou shark flavivirus in both a shark and crab host is of particular interest since the potential dual-host nature of this virus may indicate that the invertebrate-vertebrate relationship seen in other flaviviruses may have a more profound evolutionary root than previously expected. Potential endogenous viral elements and the range of novel aquatic flaviviruses discovered thus shed light on virus origins and evolutionary history and may indicate that, like terrestrial life, the origins of flaviviruses may lie in aquatic environments.
Topics: Animals; Aquaculture; Aquatic Organisms; Biological Evolution; Fishes; Flavivirus; Flavivirus Infections; Humans
PubMed: 35975997
DOI: 10.1128/jvi.00439-22 -
Viruses Nov 2014The Flavivirus genus is in the family Flaviviridae and is comprised of more than 70 viruses. These viruses have a broad geographic range, circulating on every continent... (Review)
Review
The Flavivirus genus is in the family Flaviviridae and is comprised of more than 70 viruses. These viruses have a broad geographic range, circulating on every continent except Antarctica. Mosquito-borne flaviviruses, such as yellow fever virus, dengue virus serotypes 1-4, Japanese encephalitis virus, and West Nile virus are responsible for significant human morbidity and mortality in affected regions. This review focuses on what is known about flavivirus-mosquito interactions and presents key data collected from the field and laboratory-based molecular and ultrastructural evaluations.
Topics: Animals; Culicidae; Flavivirus; Flavivirus Infections; Host-Pathogen Interactions; Humans; Insect Vectors
PubMed: 25421894
DOI: 10.3390/v6114703 -
Cell Mar 2002The first structure of a flavivirus has been determined by using a combination of cryoelectron microscopy and fitting of the known structure of glycoprotein E into the...
The first structure of a flavivirus has been determined by using a combination of cryoelectron microscopy and fitting of the known structure of glycoprotein E into the electron density map. The virus core, within a lipid bilayer, has a less-ordered structure than the external, icosahedral scaffold of 90 glycoprotein E dimers. The three E monomers per icosahedral asymmetric unit do not have quasiequivalent symmetric environments. Difference maps indicate the location of the small membrane protein M relative to the overlaying scaffold of E dimers. The structure suggests that flaviviruses, and by analogy also alphaviruses, employ a fusion mechanism in which the distal beta barrels of domain II of the glycoprotein E are inserted into the cellular membrane.
Topics: Capsid; Cryoelectron Microscopy; Dengue Virus; Humans; Hydrogen-Ion Concentration; Image Processing, Computer-Assisted; Lipid Bilayers; Membrane Fusion; Models, Molecular; Viral Envelope Proteins
PubMed: 11893341
DOI: 10.1016/s0092-8674(02)00660-8 -
The Enzymes 2021Flaviviruses such as dengue, Japanese encephalitis, West Nile, Yellow Fever and Zika virus, cause viral hemorrhagic fever and encephalitis in humans. However, antiviral...
Flaviviruses such as dengue, Japanese encephalitis, West Nile, Yellow Fever and Zika virus, cause viral hemorrhagic fever and encephalitis in humans. However, antiviral therapeutics to treat or prevent flavivirus infections are not yet available. Thus, there is pressing need to develop therapeutics and vaccines that target flavivirus infections. All flaviviruses carry a positive-sense single-stranded RNA genome, which encodes ten proteins; three structural proteins form the virus shell, and seven nonstructural (NS) proteins are involved in replication of the viral genome. While all NS proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) are part of a functional membrane-bound replication complex, enzymatic activities required for flaviviral replication reside in only two NS proteins, NS3 and NS5. NS3 functions as a protease, helicase, and triphosphatase, and NS5 as a capping enzyme, methyltransferase, and RNA-dependent RNA polymerase. In this chapter, we provide an overview of viral replication focusing on the structure and function of NS3 and NS5 replicases. We further describe strategies and examples of current efforts to identify potential flavivirus inhibitors against NS3 and NS5 enzymatic activities that can be developed as therapeutic agents to combat flavivirus infections.
Topics: Enzyme Inhibitors; Flavivirus; RNA-Dependent RNA Polymerase; Viral Nonstructural Proteins; Virus Replication
PubMed: 34696835
DOI: 10.1016/bs.enz.2021.07.006 -
Journal of Virology Nov 2021Cellular factors have important roles in all facets of the flavivirus replication cycle. Deciphering viral-host protein interactions is essential for understanding the...
Cellular factors have important roles in all facets of the flavivirus replication cycle. Deciphering viral-host protein interactions is essential for understanding the flavivirus life cycle as well as development of effective antiviral strategies. To uncover novel host factors that are co-opted by multiple flaviviruses, a CRISPR/Cas9 genome wide knockout (KO) screen was employed to identify genes required for replication of Zika virus (ZIKV). Receptor for Activated Protein C Kinase 1 (RACK1) was identified as a novel host factor required for ZIKV replication, which was confirmed via complementary experiments. Depletion of RACK1 via siRNA demonstrated that RACK1 is important for replication of a wide range of mosquito- and tick-borne flaviviruses, including West Nile Virus (WNV), Dengue Virus (DENV), Powassan Virus (POWV) and Langat Virus (LGTV) as well as the coronavirus SARS-CoV-2, but not for YFV, EBOV, VSV or HSV. Notably, flavivirus replication was only abrogated when RACK1 expression was dampened prior to infection. Utilising a non-replicative flavivirus model, we show altered morphology of viral replication factories and reduced formation of vesicle packets (VPs) in cells lacking RACK1 expression. In addition, RACK1 interacted with NS1 protein from multiple flaviviruses; a key protein for replication complex formation. Overall, these findings reveal RACK1's crucial role to the biogenesis of pan-flavivirus replication organelles. Cellular factors are critical in all facets of viral lifecycles, where overlapping interactions between the virus and host can be exploited as possible avenues for the development of antiviral therapeutics. Using a genome-wide CRISPR knockout screening approach to identify novel cellular factors important for flavivirus replication we identified RACK1 as a pro-viral host factor for both mosquito- and tick-borne flaviviruses in addition to SARS-CoV-2. Using an innovative flavivirus protein expression system, we demonstrate for the first time the impact of the loss of RACK1 on the formation of viral replication factories known as 'vesicle packets' (VPs). In addition, we show that RACK1 can interact with numerous flavivirus NS1 proteins as a potential mechanism by which VP formation can be induced by the former.
Topics: A549 Cells; Aedes; Animals; COVID-19; CRISPR-Cas Systems; Chlorocebus aethiops; Culicidae; Dengue Virus; Flavivirus; Genome-Wide Association Study; HEK293 Cells; Host-Pathogen Interactions; Humans; Neoplasm Proteins; RNA, Small Interfering; RNA, Viral; Receptors for Activated C Kinase; SARS-CoV-2; Vero Cells; Virus Replication; West Nile virus; Zika Virus; Zika Virus Infection
PubMed: 34586867
DOI: 10.1128/JVI.00596-21