Molecular Virology and Control of Flaviviruses
"a valuable resource" (Doodys)
Caister Academic Press
Novartis Institute for Tropical Diseases, Singapore 138670
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Flaviviruses are a diverse group of small RNA enveloped viruses, many of which are important human and animal pathogens. The best known include dengue virus, yellow fever virus, Japanese encephalitis virus, and West Nile virus. These viruses are endemic in many tropical and sub-tropical regions of the world. Dengue virus alone infects over 100 million people annually. In recent years, research on flaviviruses has progressed at a remarkable rate, leading to significant advances in our understanding of virus biology; this should ultimately lead to the development of better vaccine and antiviral strategies.
The editor of Molecular Virology and Control of Flaviviruses has assembled an up-to-date and cutting-edge anthology from the leading experts in the flavivirus field. Chapters are balanced by contributions from established investigators, who have dedicated their careers to flavivirus research, with those from newcomers who have recently made significant contributions to the flavivirus field. The book opens with a brief introduction then divides into two sections: Molecular Virology (Chapters 2-9) and Virus Prevention (Chapters 10-15). The first section covers: virion structure; virus replication; the NS1 glycoprotein; the NS3 protein; the NS5 protein; innate immunity and flavivirus infection; host responses to flavivirus infection; and flavivirus fitness and transmission. The second section includes: vaccines; antibody therapy; small molecule antiviral development; flavivirus diagnostics; vector-virus interactions; and vector control. The book represents an important update of flavivirus research and will serve as a reference to flavivirus researchers at the graduate level and beyond. A recommended text for all virology libraries.
"a valuable reference for experienced researchers ... This well-designed book covers the important new scientific data on pathogenic flaviviruses and will serve as a valuable resource for investigators working on methods to prevent disease from these viruses." from Doodys
Table of contents
1. Flaviviruses: Past, Present And Future
Duane J Gubler
The flaviviruses (genus Flavivirus) are among the most important pathogens infecting humans and domestic animals, causing hundreds of millions of infections annually. They have a global distribution and cause a broad spectrum of illness ranging from mild viral syndrome to severe and fatal hemorrhagic and neurologic disease. The genus is made up of a diverse group of 53 viral species that have evolved into three distinct groups with very different transmission cycles. The vector-borne group is transmitted among vertebrate hosts by hematophagous arthropods (mosquitoes and ticks), the no-known vector group is transmitted directly among vertebrate animals and the arthropod group is transmitted directly among arthropods. This chapter reviews the history, the present status and future trends of flaviviruses, using some of the more important species as case studies.
2. Flavivirus Virion Structure
Richard J. Kuhn
Flavivirus virions form in the endoplasmic reticulum (ER) with the recruitment of genome RNA, capsid protein, and the envelope (E) and precursor to the membrane proteins (prM). The nascent particles acquire a lipid bilayer as they bud into the ER lumen in an immature form. Glycosylation and subsequent processing of the particles occur as they proceed through the cellular secretory system. In the low pH that is encountered in the trans-Golgi network, cellular furin activates the particles by cleavage of prM into M. The particles are released from the cell in a mature and infectious form. The observations demonstrate the significant conformational and translational movements of the viral structural proteins during the virus life cycle and suggest the particles have substantial dynamic capabilities. These properties have been substantiated by analyses of antibody binding to virions and suggest novel targets for future therapeutic intervention strategies.
3. Flavivirus Replication and Assembly
Justin A. Roby, Anneke Funk, and Alexander A. Khromykh
The replication and assembly of Flaviviruses are complex procedures, which require the efficient coordination of a number of different steps. These stages are highly organized temporally and spatially in the infected cell and require the virus-induced establishment of host-derived membrane structures. Flavivirus RNA structures, non-structural proteins and host factors actively participate in the replication of genomic RNA within vesicle packets (VP). Progeny (+) strand RNA exits the VP pore and is incorporated into nucleocapsids by the capsid protein. Nucleocapsids are then presumably transported into the lumen of the endoplasmic reticulum at sites directly opposed to the VP pore during formation of the prM-E studded lipid envelope. These immature virions are trafficked to the Golgi network in individual vesicles for glycoprotein maturation and furin-directed prM cleavage. Mature virions (with associated, cleaved prM) are then secreted into the extracellular milieu.
4. The Many Faces of the Flavivirus Non-structural Glycoprotein NS1
David Muller and Paul R Young
The Flavivirus non-structural protein, NS1 is an enigmatic protein whose structure and mechanistic function has remained elusive since it was first identified 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 between 46 and 55 kDa depending on its glycosylation status. NS1 exists in multiple oligomeric forms and is found at different cellular locations; cell membrane associated in vesicular compartments within the cell or on the cell surface and as a secreted extracellular hexamer. Intracellular NS1 plays an essential cofactor role in virus replication and has been shown to co-localize with dsRNA and other components of the viral replication complex. However the precise function of this protein in viral replication has yet to be elucidated. Secreted and cell surface associated NS1 are highly immunogenic and either the protein or the antibodies it elicits have been implicated in both protection and pathogenesis in infected hosts. It is also an important biomarker for early diagnosis. In this review we provide an overview of these disparate areas of research.
5. The Flavivirus NS3 Protein: Structure and Functions
Dahai Luoa, Siew Pheng Lim and Julien Lescar
The non-structural protein 3 (NS3) of flaviviruses is the second most conserved amongst the viral proteins. It bears a molecular mass of 69 kDa and is endowed with multiple functions including proteolytic processing, nucleic acid duplexes unwinding, nucleoside triphosphatase (NTPase) and RNA nucleoside 5' triphosphatase (RTPase). Besides these enzymatic activities which are essential for replication of viral genomic RNA, this protein also participates in other aspects of the viral life cycle. Numerous crystal structures of apo- and ligand-bound 3D structures for the protease and helicase domains of NS3, as well as for the full-length NS3 polypeptide (NS3FL) have been determined, providing insight at the atomic level into its various enzymatic activities. In this chapter, we summarize recent progress published regarding the function and structure of this fascinating viral non-structural protein including its recently uncovered dynamic properties.
6. Structure and Function of the Flavivirus NS5 Protein
Julien Lescar, Siew Pheng Lim and Pei-Yong Shi
The non-structural protein 5 (NS5) of flaviviruses is the most conserved amongst the viral proteins. It is about 900 kDa and bears several enzymatic activities that play vital roles in virus replication. Its N-terminal domain encodes dual N7 and 2'-O methyltransferase activities (MTase), and possibly guanylyltransferase (GTase) involved in RNA cap formation. The C-terminal region comprises a RNA-dependent RNA polymerase (RdRp) required for viral RNA synthesis. Numerous crystal structures of the Flavivirus MTase and RdRp domains have been solved. MTase in complex with S-adenosyl homocysteine (SAHC) or GTP analogues showed that the domain adopts a classical 2'-O MTase fold, however, the mechanism by which the protein can perform N7-methylation is still unknown. Besides its critical enzymatic activities, NS5 has also been implicated in viral pathogenesis through phosphorylation by host cell kinases, nucleus trafficking, and interference with interferon signalling and cytokine production. Here we summarize recent progress on this highly intriguing protein.
7. Innate Immunity and Flavivirus Infection
Maudry Laurent-Rolle, Juliet Morrison and Adolfo García-Sastre
Flaviviruses, along with the distantly related Hepacivirus and Pestiviruses, belong to the Flaviviridae family. Currently, more than 70 flaviviruses have been reported, including dengue virus serotypes 1 to 4 (DENV1-4), yellow fever virus (YFV), West Nile virus (WNV), Japanese encephalitis virus (JEV) and tick-borne encephalitis virus (TBEV). Flaviviruses are significant human and animal pathogens, creating a global public health challenge with more than 100 million people infected yearly. Typical manifestations of flaviviral disease in humans include jaundice, an acute febrile illness, hemorrhagic disease, encephalitis, and even death. Currently, there are no specific antiviral treatments for infection with any of the flaviviruses. An understanding of the interplay between the virus and the host immune system would aid in the development of flaviviral therapeutics. The innate immune system is the host's first line of defense against invading pathogens. Critical components of the innate immune system include natural killer (NK) cells, the complement system, and the ability to recognize pathogens like viruses and induce antiviral cytokines. These components of the innate immune system play complementary roles in limiting viral replication and dissemination, as well as initiation of the adaptive immune response. While all flaviviruses examined thus far suppress host innate immune responses to viral infection, the mechanisms by which this occurs differ among viruses. In this chapter, we will examine the roles that the different arms of the innate immune system play in protecting the host against flavivirus infection. We will also discuss the mechanisms that flaviviruses use to subvert the innate immune system and establish infection.
8. Host Responses During Mild and Severe Dengue
Mark Schreiber, Joel Leong, and Martin Hibberd
Dengue fever is an acute viral infection that can produce a wide spectrum of disease outcomes in patients, ranging from mild or even asymptomatic fever to severe manifestations including hemorrhagic fever and shock. With the incidence of the severe forms increasing in most tropical countries as well as an overall increase in dengue incidence, dengue fever is becoming a significant burden on the health systems of affected countries. In this review, we examine the clinical definitions and presentation of mild and severe dengue as well as recent research into the underlying molecular mechanisms of the differential host response. Finally, we will examine how host responses from the early phase of the disease might be useful as biomarkers for predicting the eventual disease outcome.
9. Flavivirus Fitness and Transmission
Gregory D. Ebel and Laura D. Kramer
Flavivirus fitness is inextricably linked to the ability of a particular agent to be efficiently transmitted among relevant hosts in natural transmission cycles. Thus, fitness is an inherent component of the virus-host relationship. The mechanisms through which virus fitness is maximized are poorly understood, but have recently been examined in increasing detail. This chapter examines recent developments in the study of flavivirus fitness from both observational and experimental studies, highlighting important emergent and/or resurgent tick- and mosquito-borne members of the flavivirus genus.
10. Flavivirus Vaccines
Scott B. Halstead
Eight flaviviruses cause significant morbidity and mortality around the globe: yellow fever (YF), Japanese encephalitis (JE), Tick-borne encephalitis (TBE), dengue 1, 2, 3, 4 and West Nile (WN). Four, YF, JE, TBE and WN are zoonoses, with the consequence that vaccines are the only means of protecting humans. The successful YF 17D vaccine, introduced in 1937, produced dramatic reductions in epidemic activity. Effective killed JE and TBE vaccines were introduced in the middle of the 20th century. Unacceptable adverse events have prompted change from a mouse-brain killed JE vaccine to safer and more effective second generation JE vaccines. These may come into wide use to effectively prevent this severe disease in the huge populations of Asia - North, South and Southeast. The dengue viruses produce many millions of infections annually due to transmission by a successful global mosquito vector. As mosquito control has failed, several dengue vaccines are in varying stages of development. A tetravalent chimeric vaccine that splices structural genes of the four dengue viruses onto a 17D YF backbone is in Phase III clinical testing. For each of the eight flaviviruses, clinical disease, epidemiology, vaccine development history, vaccine useage, precautions and adverse events are briefly presented.
11. Antibody Therapeutics Against Flaviviruses
Michael S. Diamond, Theodore C. Pierson, and John T. Roehrig
Flaviviruses are a group of small RNA enveloped viruses that cause severe disease in humans worldwide. Recent advances in the structural biology of the flavivirus envelope proteins and virion have catalyzed rapid progress toward understanding how the most potently inhibitory antibodies neutralize infection. These insights have identified factors that modulate the potency of neutralizing antibodies and provided insight into the design of novel antibody-based therapeutics against several members of the flavivirus genus. This chapter will discuss recent advances in the understanding of the mechanisms of antibody neutralization of flaviviruses, and review the progress towards development of antibody-based therapeutics against several different flaviviruses of global concern.
12. Flavivirus Antiviral Development
Qing-Yin Wang, Yen-Liang Chen, Siew Pheng Lim, and Pei-Yong Shi
Many flaviviruses are human pathogens of global importance, but no clinically approved antiviral therapy is currently available to manage these diseases. Both pharmaceutical industry and academia have invested considerable efforts over the past decade on finding the flavivirus antivirals using modern drug discovery. Various high-throughput compatible target-based and cell-based assays have been developed and implemented. In this chapter, we describe in details the methodologies developed for screening inhibitors against dengue virus, and the lessons learned from our screening campaigns. Based on our experience on dengue virus and the status of hepatitis C virus drug discovery, we propose that a combined target-based approach (e.g., viral polymerase, protease, and envelope) and a cell-based approach (e.g., virus infection and replicon assays) should be persistently pursued to develop flavivirus antiviral therapy.
13. Flavivirus Diagnostics
Within the family of Flaviviridae there are many medically important viruses that cause human disease worldwide. These viruses were originally categorized based on phenotype due to their antigenic relatedness and placed within groups, subgroups and types and later confirmed with nucleic acid sequence analysis. Diagnosis of disease caused by flaviviruses has been primarily based on serological identification of anti-viral antibodies and virus isolation. Some of the classic serological techniques of hemagglutination inhibition assay and complement fixation were replaced with the enzyme linked immunosorbent assay (ELISA) for the detection of IgM, IgG and IgA antibodies primarily due to ease-of-use. The plaque reduction neutralization test (PRNT) provided the specificity needed for virus identification following a positive serological test by ELISA. The development of polymerase chain reaction (PCR) assays improved the ability to detect virus nucleic acid sequence when viral isolates were not obtained. Because reverse transcriptase PCR (RT-PCR) assays are easy to perform, have increased sensitivity and provide virus identification in a short period of time, RT-PCR has essentially replaced isolation techniques for rapid diagnosis. However, virus isolation is still essential for genetic analysis. The future of flaviviral disease diagnosis is new platforms for antibody and nucleic acid detection as well as the development of point-of-care diagnostics for clinical management
14. Flavivirus-Vector Interactions
Ken E. Olson and Carol D. Blair
Flaviviruses such as dengue, yellow fever and West Nile viruses continue to cause a significant amount of disease in humans. Most flaviviruses are maintained in nature by cycling between hematophagus arthropod vectors and vertebrate hosts, and the viruses need to replicate in both vectors and hosts. This review focuses on flavivirus-vector interactions to present a current understanding of events and processes that lead to vector infection, virus amplification and dissemination, transmission. This chapter will focus mainly on DENVs and their interactions with Aedes aegypti, but will include interactions between other flaviviruses and their vectors where approriate. Flavivirus-mosquito cell interactions will be discussed first to give the reader a cellular view of the infection process but this will be followed with a view of the infection process in vectors. This review will describe flavivirus interactions with the vector's innate immune (Toll, Jak-Stat, apoptosis) and antiviral (RNA interference) pathways and discuss flavivirus evolution and its consequences for vector infection, DENV transmission and genotype displacement. The review will dicuss how our understanding of vector genetics is enhanced by the availability of genome databases for A. aegypti and Culex quinquefasciatus, tissue-specific transcriptomes and microarrays and small RNA databases. The chapter will also discuss RNA silencing and vector transgenesis as tools for defining gene function. Finally, we will review several recently described vector-based approaches that may result in new strategies for flavivrus disease control.
15. Vectors of Flaviviruses and Strategies for Control
Lee-Ching Ng and Indra Vythilingam
Recent worsening of global dengue situation, geographical spread of the West Nile virus to the United States and the unexpected emergence of the Zika virus on the Yap island in the Pacific, have placed mosquito-borne flaviviruses in the limelight. Vector control remains as a key measure for prevention and control of these diseases. Mosquito borne flaviviruses are vectored by an array of mosquito species, with different behaviour and habitats. This chapter discusses the principles of vector control using Singapore's dengue control programme to illustrate a strategy for urban peridomestic Aedes mosquitoes; and control of rural WNV and JEV to demonstrate strategies for rural Culex mosquitoes. In both situations, the incorporation of measures that consider the complex interplay of factors, including disease ecology, vector bionomics, land use, human activities and other social economic development, is essential. Despite the different strategies demanded by different vectors of diverse ecology and bionomics, the organisational framework that guide vector control remains consistent. The management system demands cost-effectiveness, which seeks synergies among the various tools used, and among various stakeholders. Sustainability, insecticide resistance and negative impact on the environment remain as some of the challenges faced by vector control programmes.
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(EAN: 9781904455929 9781910190999 Subjects: [microbiology] [virology] [medical microbiology] )