Viruses and Interferon: Current Research
"a series of thorough reviews" (ISICR Newsletter)
Caister Academic Press
Infectious Diseases Division, McMaster University, Hamilton, Ontario, Canada
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Interferons (IFNs) play pivotal roles in shaping the immune responses in mammals and are particularly important for the control of viral infections and cell growth, and immune regulation. These proteins rapidly induce an 'anti-viral state' in cells that surround infected cells. In order to survive, viruses have evolved multiple strategies to evade the anti-viral effects of IFNs. Elucidating the molecular and cellular biology of the virus-interferon interaction is key to understanding issues such as viral pathogenesis, latency, and the development of novel antivirals.
In this book, a panel of international experts reviews the current hot-topics, producing a timely overview of this exciting field. The book opens with a chapter that comprehensively reviews the antiviral effects of extracellular double-stranded RNA, the 'viral toxin'. This is followed by chapters that review the properties of type I and type III interferons, and the role of interferon-stimulated genes. The next five chapters are devoted to understanding the diverse strategies used by clinically relevant human viruses to subvert host interferon responses. The closing chapter provides an interesting overview of the clinical application of interferon as antiviral and anticancer agents. Essential reading for every scientist involved in interferon or antiviral research and a recommended text for all virology laboratories.
"Dr. Mossman has convinced many of the leaders in this field of research to contribute to this book ... has done an excellent job of putting together a series of thorough reviews that focus on a specific topic and are well written. This book will be of value to those individuals who want a source of focused information on how the innate interferon response to viral infection has evolved and how the attacking viruses have similarly developed mechanisms to evade the interferon response." from ISICR Newsletter
Table of contents
1. The antiviral effects of extracellular dsRNA
Stephanie J. DeWitte-Orr and Karen L. Mossman
Viral double-stranded RNA (dsRNA), a replication by-product of almost all viruses, has been studied for over 55 years, first as a toxin, then as a type I IFN inducer, a viral mimetic and an immunomodulator for therapeutic purposes. Not only does dsRNA function as a pathogen associated molecular pattern (PAMP), sensed by host germline encoded pattern recognition receptors (PRRs) to stimulate innate immune responses, it also acts as a bridge to activate antiviral adaptive immune responses. DsRNA is generated intracellularly during a virus infection, but is released into the extracellular space during cell lysis. This review will focus on the structure and generation (both endogenous and viral) of extracellular dsRNA, and the host sensing mechanisms that result in type I IFN- and RNAi-mediated antiviral responses. The possible therapeutic applications of these findings will also be discussed. The goal of this review is to highlight the importance of this unique nucleic acid, with a focus on how its extracellularity influences its effects on the host and how these effects can be manipulated for our therapeutic purposes.
2. Type I interferon production by viruses
Kazuhide Onoguchi, Kiyohiro Takahasi, Mitsutoshi Yoneyama, and Takashi Fujita
Type I interferon (IFN) is produced in variety of tissues in the body. It has been known that viral infection efficiently induces type I IFN. Bacterial endotoxin and double stranded (ds) RNA are representative non-viral inducers. Recent works revealed that cellular receptors for Pathogen Associated Molecular Patterns (PAMPs) are responsible for triggering IFN production. In the case of virus infection, RNA molecules encoded by viruses are sensed by the PAMPs receptors. Different viruses preferentially activate different sensor molecules. Current knowledge on virus- or RNA pathogen-specificity as well as structure-function relationship of RNA sensing is summarized. Furthermore, numerous signaling adaptors are reported to participate in the regulation of IFN gene activation.
3. Type III interferons in antiviral immunity
Srikanth Chiliveru and Søren R. Paludan
Virus infections stimulate host immune responses characterized by production of interferons (IFNs). The identification of IFN-λ (alternatively termed interleukin 28A/B, -29 or type III IFNs) has revealed that the immune response to viruses has more components than the type I IFNs known for more than 50 years. IFN-λs are known to have type-I-IFN-like biological activities, but our understanding of these novel players in the antiviral response is still under development. In this chapter, we describe the current knowledge on expression and function of type III IFNs in innate antiviral immune defenses and discuss recent findings proposing IFN-λ to shape the adaptive immune response. We suggest that type III IFNs are key antiviral cytokines exerting direct antiviral functions at epithelial surfaces at the early stages of infection, and that this class of cytokines also promotes antigen-specific cytotoxic activity of CD8+ T lymphocytes at later stages of the antiviral immune response.
4. Antiviral function of interferons
Marisela Rodriguez, Jessica A. Campbell and Deborah J. Lenschow
The type I interferon (IFN) system plays a critical role in limiting the spread of viral infection. Viruses induce the production of IFN-α and β, which bind to the IFN-α/ β receptor (IFNAR) and trigger the JAK/STAT signaling cascade. The ensuing induction of IFN-stimulated genes (ISGs) inhibits viral replication by targeting multiple points in the viral life cycle. ISGs exert their antiviral function through diverse mechanisms, including activities directly targeting the virus such as the degradation of viral RNA, the inhibition of translation, the blockade of virion release, and actions that modify the host response including regulation of the IFN response, NF-κB signaling, and apoptosis, among others. This chapter reviews several ISGs that have been shown to mediate antiviral activity either in vitro or in vivo, and in some cases, both. The mechanisms by which individual ISGs confer cellular protection are summarized, although the effector pathways of certain ISGs are still being delineated. The study of ISGs continues to provide important contributions to our understanding of the host-virus interface and the cellular antiviral response.
5. Host interferon: A silent partner in the regulation of herpes simplex virus latency
William P. Halford and Bryan M. Gebhardt
Herpes simplex virus (HSV) establishes latent infections as a consequence of a non-cytolytic immune response that represses HSV replication, but fails to destroy neurons that harbor HSV's genetic material. It has become increasingly evident that, in both mice and men, the host interferon system plays a critical role in tipping HSV's latency-replication balance in favor of latency. HSV can resist interferon-induced repression provided that HSV's two interferon antagonists, ICP0 and ICP34.5, are synthesized. Failure to synthesize either protein renders HSV interferon-sensitive and prone to establishing latent infections. Intriguingly, ICP0 and ICP34.5 are encoded within HSV's latency-regulating RL regions. We propose that differential synthesis of ICP0 and ICP34.5 may endow HSV with the capacity to 'choose' between latency and replication in vivo. HSV may choose to establish a latent infection by downregulating ICP0 or ICP34.5, and render itself sensitive to the interferon-induced antiviral state. Conversely, synthesis of ICP0 and ICP34.5 may ensure that HSV resists interferon-induced repression and completes another cycle of replication.
6. Poxviruses and interferons
Beatriz Perdiguero and Mariano Esteban
Since the discovery of interferons (IFNs) more than half a century ago, these molecules have become key players of many cellular processes, particularly in the control of viral infections, cell growth and immune regulation. How the cells respond to IFN and identification of the molecular signals involved is a major goal in research. In this chapter we address these issues through the current understanding of the interaction between poxviruses and the IFN system. These large DNA containing viruses have acquired during their evolution an array of genes that counteract the IFN pathways at multiple levels. How the viral genes act is presented.
7. Evasion of interferon responses by hemorrhagic fever viruses
Christopher F. Basler and Gaya K. Amarasinghe
Viral hemorrhagic fever, a clinical syndrome characterized by fever, shock and bleeding, can be caused in humans by members of several RNA virus families, including filoviruses, bunyaviruses, arenaviruses and flaviviruses. None of the hemorrhagic fever viruses uniformly cause hemorrhage in humans. However, some viruses show greater propensity to cause severe, life threatening disease than do others. Because of their potential to cause life threatening disease, these viruses are public health concerns and many of the hemorrhagic fever viruses are considered to be potential weapons of terror. Recent emphasis on these viruses has prompted research into the mechanisms by which they interact with and evade host innate immune responses, particularly antiviral interferon (IFN) responses. Research has identified a variety of mechanisms of innate immune antagonism, and data from filovirus and bunyavirus systems links these functions to virulence. This sets the stage for studies to evaluate how specific mechanisms of IFN evasion contribute to the clinical manifestations of viral hemorrhagic fever.
8. Influenza virus and interferons
Gijs A. Versteeg and Adolfo García-Sastre
Influenza viruses are the etiological agents of seasonal influenza outbreaks as well as three devastating influenza pandemics in the 20th century and the 2009 swine-origin H1N1 pandemic. Like most viruses that cause significant disease, influenza viruses have developed means to circumvent the induction and effects of the innate immune system. Unlike most other RNA viruses, influenza viruses replicate in the nucleus, rather than in the cytoplasm. This distinguishing feature makes the interactions of influenza viruses with their hosts both complex and unique, and requires a well-orchestrated manipulation of many cellular processes. This includes the interferon (IFN) response, a key innate immune pathway, critical for limiting virus replication. To cope with the IFN burden, influenza viruses express non-structural protein 1 (NS1), which is largely dedicated to antagonism of the host IFN response. This chapter describes how influenza viruses induce the IFN response and the ample means they have developed to intersect with it at all three stages of the pathway. The molecular details of NS1-mediated IFN antagonism are discussed, as well as new vaccination and antiviral drug strategies that target NS1 to attenuate virus replication.
9. Hepatitis C virus regulation of interferon antiviral defenses
Helene MinYi Liu and Michael Gale Jr
Mammalian cells respond to virus challenge by initiating an intracellular innate immune response that is designed to limit virus replication and to inform and modulate the ensuing adaptive immune response. Innate immune defenses are characterized by pathogen recognition receptor signaling that mediates the expression of antiviral gene products, the production of interferon α/β (IFN) and interferon-stimulated genes, and the secretion of other proinflammatory cytokines from the site of infection. Hepatitis C virus (HCV) confers a chronic infection of the liver in nearly 200 million people around the world. Hepatic innate immune defenses impose the front line of protection against HCV replication and pathogenesis. HCV infection is treated with IFN-based therapy. However, HCV most often evades hepatic innate immunity and responds overall poorly to therapy to thereby persist and a run a chronic disease course. HCV persistence has been linked to a complex combination of virus-host interactions that disrupt intracellular innate immune signaling pathways and attenuate the antiviral actions of IFN. Viral regulation of these processes breaks a critical cross-talk between innate and adaptive immunity to attenuate antiviral immune defenses and provide a foundation for chronic HCV infection.
10. Clinical application of interferons
Ben X. Wang, Ramtin Rahbar and Eleanor N. Fish
In this chapter, the clinical uses of interferons (IFNs), predominantly the IFN-αs, will be reviewed in the context of virus infections and neoplasias. The last 30 years have seen an accumulation of clinical studies evaluating the potential safety and efficacy of IFN treatment for acute and chronic virus infections, most notably hepatitis C virus. Moreover, given the pleiotropic effects of type I IFNs in terms of their antiproliferative and apoptotic effects, their anti-angiogenic effects and their ability to modulate an immune response specifically activating dendritic cells, cytolytic T cells and NK cells, their therapeutic potential for the treatment of a wide variety of leukemias and solid tumors has received intensive investigation.
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(EAN: 9781904455813 9781912530670 Subjects: [virology] [microbiology] [medical microbiology] [molecular microbiology] )