Influenza viruses are important pathogens responsible for flu epidemics and pandemics. The socio-economic impact of seasonal flu is very significant and the rapid rate of virus evolution necessitates the development of new vaccines every year. Another major challenge is the emergence of novel strains that are highly pathogenic for humans. Examples include H7N9 and H5N1 (emerged from birds) which have mortality rates of up to 30% and 60%, respectively. Research is underway to develop of a universal flu vaccine that would provide long-lasting protection and be effective against emergent strains.
Following on from their highly-acclaimed 2010 book, Drs. Wang and Tao present a new, up-to-date and comprehensive review of current advancements in molecular influenza virology. Topics covered include: stem-specific broadly neutralizing antibodies to the virus hemagglutinin; virus replication and transcription; influenza B virus hemagglutinin; influenza A virus ribonucleoprotein complex; regulation of the virus replication machinery by host factors; evolution of receptor specificity of influenza A virus hemagglutinin: PB1-F2, a multi-functional non-structural influenza A virus protein; and avian influenza H7N9 virus.
Highly informative and well referenced, this book is essential reading for all influenza specialists and is recommended reading for all virologists, immunologists, molecular biologists, public health scientists and research scientists in pharmaceutical companies.
Table of contents
1. Stem-specific Broadly Neutralizing Antibodies of Influenza Virus Hemagglutinin
Fengyun Ni and Qinghua Wang
Pages: 1-16.
The past few years have witnessed a substantial advance in identifying novel antibodies that target conserved structural elements on influenza hemagglutinin, the receptor-binding site and the stem domain, thus revived the hope for universal antibody. This chapter reviews the isolation of stem-specific bnAbs, the structural basis of bnAb-mediated virus neutralization, and the novel strategies for eliciting bnAbs in vivo.
2. Influenza Virus Replication and Transcription
Jaime Martin-Benito, Frank T. Vreede and Juan Ortin
Pages: 17-40.
The influenza A viruses are members of the Orthomyxoviridae family that cause respiratory infections in humans. They appear as yearly epidemics and occasional pandemics, which constitute a serious health problem and generate an important economic burden. The virus genome consists of eight single-stranded, negative-polarity RNAs that associate to the RNA polymerase complex and the nucleoprotein to form megaDalton sized ribonucleoprotein particles (RNPs). Here we describe the structure of these RNPs, their constitutive elements and the interactions among them. In addition, we discuss the mechanisms by which the RNPs transcribe and replicate the viral genome, including the potential participation of cellular host factors.
3. Recent Progress in Understanding Influenza B Virus Hemagglutinin
Fengyun Ni and Qinghua Wang
Pages: 41-54.
This chapter focuses on recent progress in understanding influenza B virus hemagglutinin (HA) in three aspects: the roles of Phe-95 in receptor binding and host tropism, the structural basis of the divergent evolution, and the membrane-fusion mechanisms as compared to influenza A virus HA.
4. Structure and Assembly of the Influenza A Virus Ribonucleoprotein Complex
Wenjie Zheng, Wenting Zhang, Yusong R. Guo and Yizhi Jane Tao
Pages: 55-76.
The genome of the influenza A virus as well as other orthomyxoviruses is comprised of eight segments of single-stranded, negative-sense RNA that are encapsidated as individual rod-shaped ribonucleoprotein complexes (RNPs). Influenza A virus RNPs play critical roles during virus infection by directing viral RNA replication and transcription, intracellular trafficking of the viral RNA, gene reassortment as well as genome packaging into progeny viruses. Biochemically each RNP contains a viral RNA, a viral polymerase and multiple copies of the viral nucleoprotein (NP). Built on over 40 years of intensive research, exciting developments in recent years have substantially enhanced our understanding of the structure and function of various molecular components of RNP as well as the double-helical RNP structure itself.
5. Host Factors Regulating the Influenza Virus Replication Machinery
James Kirui, Vy Tran and Andrew Mehle
Pages: 77-100.
The influenza replication machinery drives gene expression and genome replication. Whereas the viral polymerase contains all of the intrinsic enzymatic activity required for these processes, it is dependent upon interactions with host cell factors for a successful infection. Here we describe the host factors that have been shown to interact with and modulate the viral polymerase. These include host factors repurposed by the virus, factors whose normal activites have been disrupted, viral and host proteins that regulate polymerase function, and host mechanisms that antagonize the viral replication machinery in an unsuccessful attempt to stop replication.
6. Receptor Specificity in Surveillance of Natural Sequence Evolution of Influenza A Virus Hemagglutinin
Rahul Raman, Kannan Tharakaraman, Zachary Shriver, Akila Jayaraman, V. Sasisekharan and Ram Sasisekharan
Pages: 101-120.
Influenza A viruses are rapidly evolving pathogens with potential for novel strains to emerge and cause human pandemics. H1N1, H2N2 and H3N2 influenza A virus (known as human viruses) hemagglutinin (HA) binds to glycan receptors in the human upper respiratory epithelia that are terminated by a2,6-linked sialic acid (also known as human receptors), a critical feature that permits the virus to efficiently infect and transmit via aerosol in humans. The avian-adapted H5N1, H9N1, H7N7, H7N2 and H7N9 have shown binding to human receptors, cause severe infections in humans and are rapidly evolving in various species but are yet to adapt to the human host to establish sustained circulation. There is a need to better understand and differentiate glycan receptor binding properties between these avian-adapted and human viruses. This chapter offers perspectives on structural and biochemical analyses of HA-glycan receptor interactions from standpoint of distinguishing receptor specificity of human and avian viruses and also in the context of their natural evolution. The perspectives offered in this chapter are intended to expand the current thinking and hence understanding of HA-glycan specificity to facilitate improved surveillance and preparedness in the event of an emergence of a novel strain with pandemic potential.
7. PB1-F2: A Multi-functional Non-structural Influenza A Virus Protein
Eike R. Hrincius and Jonathan A. McCullers
Pages: 121-138.
A central determinant of pathogenicity for influenza A virus (IAV) infections is the interplay of the invading virus with the host immune system. The host has to recognize and fight the invading pathogen; at the same time the induced immune reaction has to be well balanced and not self-destroying. Influenza viruses have evolved strategies to support their replication and to circumvent host immune responses. The PB1-F2 protein of IAVs, a nonstructural protein only found within the infected cell, has had manifold functions attributed to it. The protein's proposed support of virus replication, together with modulation of immune responses, categorize PB1-F2 as a classic multi-functional viral protein. Shortly after its discovery it became obvious that PB1-F2 has the potential to mediate pathogenicity upon primary viral infection and also during bacterial co-infections. This effect appears to be mediated by induction of cell death, promotion of cytokine release and inflammation, and/or modulation of interferon responses in a virus, cell type, and host-specific manner. Because these functions of PB1-F2 are poorly understood and this protein has not been as well studied as other influenza virus proteins, research efforts need to be intensified to clarify the role of PB1-F2 in influenza virus infections.
8. Avian Influenza H7N9 Virus
Ying Wu, Yi Shi, Jun Liu, Yan Wu and George F. Gao
Pages: 139-160.
In March 2013, the first cases of human infection with a novel reassortant of avian influenza A virus (H7N9) were reported in China. The rapid increase in cases with considerable morbidity and mortality over a subsequent brief time period has posed a great threat to public health globally. In this chapter we present an overview of the current understanding of H7N9 virus from the perspectives of the virus origin, clinical features and treatments of virus infection, host immune responses, virus receptor-binding properties as well as drug resistance. We also provide a snapshot of vaccine development and monoclonal antibody application against H7N9 virus infection and call for precautionary measurements for unpredictable emergence of novel reassortants of influenza viruses, HxNy.