Alphaviruses: Current Biology
"up-to-date review of the field" (Aus. Vet. J.)
Caister Academic Press
, Lara Herrero1
and Belinda Herring2
1Institute for Glycomics, Griffith University, Gold Coast Campus, QLD 4222, Australia; 2Sydney Medical School, C24 - Westmead Hospital, The University of Sydney, NSW 2006, Australia
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Alphaviruses comprise a fascinating group of small, enveloped single-stranded positive-sense RNA viruses. They are usually transmitted by arthropod vectors (usually mosquitoes). Of the thirty known species, eight are important human pathogens (e.g. Venezuelan equine encephalitis virus) whilst one, salmonid alphavirus, is of economic importance to the farmed fish industry. Due to their small size alphaviruses have historically been utilised as model systems for the analysis of viral pathogenesis. Understanding alphavirus molecular biology, pathogenesis and host interactions are key areas of research that have applications not only in disease prevention but also in permitting the exploitation of certain alphaviruses, e.g. Semliki Forest virus, as efficient gene therapy and/or vaccine delivery vehicles.
This timely book provides a comprehensive overview of the latest developments in alphavirus research. Written by a team of prominent scientists the main focus is on the pathogenesis and host interactions. Topics covered include: genome structure and replication; viral evolution; laboratory diagnosis and detection; interaction with the interferon system; antiviral responses in mosquitoes; animal models of alphavirus-induced inflammatory disease; clinical manifestations of arthritogenic alphaviruses; encephalitic alphaviruses; the application of alphavirus vectors for gene therapy; and chikungunya virus pathogenesis and the development of control strategies.
As the first to focus exclusively on alphaviruses, this book serves as an invaluable resource for researchers and clinicians working with alphaviruses and related viruses. Essential reading.
"The three editors of this book have led a team of twenty-four scientists ... to produce this up-to-date review of the field ... providing a thoughtful and critical introduction to the field and in identifying some of the more interesting emerging areas ... (The book) utilises the knowledge and experience of the authors to select, critically evaluate and synthesise the information into a coherent text that summarises current knowledge and points the way to future research opportunities and likely developments with this important group of viruses. It would be a great starting point for a post-graduate student commencing research in this field." from Australian Veterinary Journal
Table of contents
1. Alphavirus Genome Structure and Replication
Belinda L. Herring, Lara J. Herrero, Weiqiang Chen, Kuo-Ching Sheng, Nestor E. Rulli and Suresh Mahalingam
The family Togaviridae consists of two genera, Alphavirus and Rubivirus (Fields et al., 2013). The organization of their respective genomes is similar, but phylogenetic analysis shows that alphaviruses and rubiviruses are quite divergent (Koonin and Dolja, 1993). This book focuses on the genus Alphavirus, which consists of small (45 to 75 nm in diameter), enveloped viruses, typically transmitted by arthropod vectors, including mosquitoes, mites and ticks (Powers et al., 2001). Approximately 30 species of Alphavirus have been identified and differentiated into seven groups based on antigen similarity determined by serum neutralization. These antigenic groups are the Barmah Forest complex, the Ndumu complex, the Middelburg complex, Semliki Forest complex, Western equine encephalitis complex, Eastern equine encephalitis complex, and Venezuelan equine encephalitis complex (Powers et al., 2001). All seven serotypes share similarity in both genome organization (having two open reading frame encoding both the structural and nonstructural proteins) and viral replication cycle (which includes virus binding, entry, replication and release). This chapter will focus on the alphaviral genome and the events of alphaviral replication.
2. Alphavirus Evolution
Lark L. Coffey, Scott C. Weaver and Naomi Forrester
Alphaviruses exhibit a near-global distribution and use many vertebrates and arthropods as hosts. This chapter will discuss biological properties and phylogenetic relationships of the alphaviruses and patterns of alphavirus evolution marked by genetic changes that influence infectivity and promote emergence in epizootics and epidemics.
3. Laboratory Diagnosis and Detection of Alphaviruses
Alphaviruses have been the cause of significant morbidity and mortality in both humans and animals. While infection is suspected clinically it cannot be confirmed without the use of laboratory testing. Laboratory diagnostic techniques have changed dramatically in recent years. The advent of nucleic acid testing has increased our understanding of these viruses and provided a means of rapid diagnosis in the viraemic phase of illness. The development of various ELISA techniques has significantly improved the speed and accuracy with which antibody can be detected, providing an inexpensive means of diagnosing recent infection in both humans and animals. However, the older techniques for both antibody and antigen detection still have value and should not be discarded or relegated to history. This chapter discusses the use of traditional and modern techniques suitable for detecting and diagnosing alphavirus infections.
4. The Interaction of Alphaviruses with the Interferon System
William B. Klimstra and Kate D. Ryman
As reviewed elsewhere in this volume, the Alphavirus
genus of the family Togaviridae includes a number of important human and zoonotic pathogens that cause a variety of diseases, ranging from asymptomatic through mild, self-limiting febrile disease to polyarthritis/arthralgia (see chapter 7 for details of arthritogenic alphaviruses) or fatal encephalomyelitis (see chapter 8 for details of encephalitic alphaviruses), depending upon the virus. In traditionally used cell lines of murine or primate origin, however, wild-type alphaviruses tend to replicate rapidly. While the synthesis of virus proteins by host translation machinery is highly efficient, and thousands of progeny virions are released from each infected cell within 18-24 hours post-infection, host gene expression is almost completely arrested within a few hours via
independent inhibition of transcription and translation. Consequently, in vitro
the antiviral stress responses of the permissive host cell are very effectively suppressed by most, if not all, wild-type alphaviruses. In contrast, in vivo
the relative ability of each alphavirus to resist or evade inhibition by the type I interferon (IFN)-mediated antiviral response is arguably the most important factor determining virus virulence, and this can be reproduced to some degree in vitro
by using cell types relevant to the pathogenesis of each virus and maintaining the differentiated phenotype of such cells as completely as possible.
In this chapter, in order to understand the mechanisms involved in alphavirus virulence/attenuation, we will place in context recent findings about the interactions between the alphaviruses and the IFN-α/β system at the host, cellular and molecular levels. The current status of our knowledge in these areas is described in the following sections, focusing first from the host's perspective on IFN-α/β induction and effector mechanisms, and then on the mechanisms employed by the alphaviruses to inhibit, resist or avoid these responses.
5. Alphaviruses and their Role in Elucidating Antiviral Responses in Mosquitoes
Melanie McFarlane and Alain Kohl
The interaction between mosquito vectors and arthropod-borne viruses (arboviruses) such as alphaviruses of the Togaviridae family has long been of central interest to virologists. Indeed, the infection-induced processes and outcomes appear to differ considerably between vertebrate and arthropod hosts. Control of arbovirus infection in mosquitoes by host immune responses is beginning to be elucidated. Much of this progress is due to research using alphaviruses. Additionally, the detailed understanding of their replicative processes, and also the sophisticated molecular tools available to manipulate these viruses, have been used to great advantage. This chapter will give insights into the interactions of alphaviruses with vector immunity, and the nature of these responses.
6. Animal Models of Alphavirus-induced Inflammatory Disease
Lara J. Herrero, Adam Taylor, Pierre Roques, Brett A. Lidbury and Suresh Mahalingam
Animal models that reflect key aspects of human disease are invaluable tools for understanding the mechanisms of disease pathogenesis and development of treatment strategies. In particular, animal models play important roles in expanding the current understanding of the pathobiology of alphavirus infection. Alphaviruses are arthropod-borne viruses that are able to infect a variety of vertebrate hosts. In humans, infection can result in extensive morbidity and mortality. As the global distribution of alphaviruses expands, with recent outbreaks in new areas of the world, there is an overwhelming need to improve our understanding of alphavirus pathogenesis with the key objective of anti-alphaviral drug design. This chapter focuses on the application of alphaviral animal models with particular emphasis on how these models have expanded the understanding of disease mechanisms and have provided a foundation for the development of new treatments.
7. Clinical Manifestations of Arthritogenic Alphaviruses
Lara J. Herrero, Adam Taylor, Suan Sin Foo, Lynden Roberts, Natkunam Ketheesan and Suresh Mahalingam
Increasing geographical range and the ability of alphaviruses to cause major disease outbreaks highlight their growing importance in clinical practice. Alphaviruses are now the most common cause of infectious arthritis worldwide. A significant number of symptomatic infections result in arthralgia that can incapacitate for weeks. Acute manifestations are often severe and highly debilitating, affecting multiple joints. Furthermore, rheumatic symptoms may persist for months. Chronic arthritis has also been described; however, symptoms beyond 3-6 months can usually be attributed to an alternative disease. Fatigue and malaise often accompany the infection-related arthritis, causing high morbidity, which has an important economic impact. In this chapter, the clinical manifestations associated with some of the more important arthritogenic alphaviruses are described.
8. Encephalitic Alphaviruses
Clive S. McKimmie and John K. Fazakerley
Alphaviruses are a group of medically important viruses spread by arthropods. Recent years has witnessed an increase in their geographic range and the number of infections. Following inoculation by infected arthropods, alphaviruses rapidly replicate in peripheral tissues, giving rise to a high titre plasma viremia. In the majority of cases this results is an otherwise asymptomatic infection, but in some can progress to life-threatening encephalitis. Well-characterised animal models have demonstrated that virus spreads to the brain, primarily infecting neurons, often as perivascular foci of infection. Virus infection of neural tissue triggers an influx of inflammatory mediators that, depending on a combination of virus and host factors, results in either death or clearance of infectious virus by neutralising high affinity immunoglobulins. Following clearance of brain virus, lesions of T cell-driven demyelinating inflammation can result. In the absence of efficacious vaccines or specific medical treatments for alphavirus infection, a better understanding of its pathogenesis will aid the design of novel therapies.
9. Application of Alphavirus Vectors for Gene Therapy
Alphavirus vectors based on Semliki Forest virus (SFV), Sindbis virus (SINV) and Venezuelan equine encephalitis virus (VEEV) have been engineered for efficient expression of heterologous proteins. In particular, SFV-based vectors have been frequently used for expression of membrane proteins in drug discovery. Likewise, SFV and SINV have been employed for numerous applications in neuroscience research due to their neurotrophic properties. Furthermore, all three alphaviruses have been used for vaccine development against infectious diseases and cancer. Alphavirus vectors have also found applications in gene therapy, especially in cancer therapy, due to their broad host range, high expression levels and transient nature. SINV vectors have demonstrated natural targeting to tumors whereas SFV vectors have been modified to enhance delivery to tumor tissue. Furthermore, oncolytic SFV vectors have been evaluated for increased therapeutic efficacy.
10. Case Study: Chikungunya Virus
Lisa F.P. Ng
The development of new and effective approaches to combat CHIKV infection is highly desirable. Molecular biology and genomic approaches could provide a brand new research paradigm. Nonetheless, to progress, potential drug candidates should also be extended to treat arthralgia and related chronic systemic inflammation induced by CHIKV. Whether these approaches will reach the clinic remains to be determined, but their success will rely on a better understanding of basic mechanisms of CHIKV infection and immunity. This chapter provides an overview of the cellular and molecular mechanisms of CHIKV pathogenesis and the various approaches leading to intervention.
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(EAN: 9781910190159 9781910190166 Subjects: [microbiology] [virology] [medical microbiology] [molecular microbiology] )