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Centenary of the 1918 influenza pandemic

2018 marks the 100th anniversary of the 1918 influenza pandemic, which claimed ~50 million lives. The introduction of influenza viruses and subsequent adaptation to humans, which enabled human-to-human transmission, continues to pose a constant threat of a future pandemic. Despite the efforts to develop antiviral drugs and vaccines, improved surveillance and prevention strategies, influenza viruses continue to circulate in human populations and cause seasonal influenza epidemics around the world each year. In light of the rapid evolution of the virus, globalization, the growing human population and the magnitude of intercontinental travel, outbreaks on the scale of the 1918 influenza pandemic would even today have a devastating effect. This collection includes Reviews and Research articles from across the Nature group of journals to showcase the latest advances in our understanding of influenza virus biology, evolution and adaptation, and advances in surveillance and drug and vaccine development. 

Reviews

Seasonal influenza viruses continue to cause epidemics each year. In this Review, Petrova and Russell discuss recent advances in understanding the molecular determinants of influenza virus immune escape, sources of evolutionary selection pressure, population dynamics of influenza viruses and prospects for better influenza virus control.

Review Article | | Nature Reviews Microbiology

In this Review, te Velthuis and Fodor detail the recently obtained high-resolution structures of the influenza virus RNA polymerase and the insights that have been gained into the mechanisms of viral transcription and replication. They also discuss how these structural data could help to identify novel antiviral targets.

Review Article | | Nature Reviews Microbiology

In this Review, McDonaldet al. describe the mechanisms and outcomes of reassortment for three well-studied viral families — Cystoviridae, Orthomyxoviridae and Reoviridae— and discuss how these findings provide new perspectives on the replication and evolution of segmented RNA viruses.

Review Article | | Nature Reviews Microbiology

The shift in the receptor-binding specificity of influenza A viruses is mostly determined by mutations in viral haemagglutinin. In this Review, Gao and colleagues discuss recent crystallographic studies that provide molecular insights into haemagglutinin–host receptor interactions that have enabled several influenza A virus subtypes to 'jump' from avian to human hosts.

Review Article | | Nature Reviews Microbiology

Influenza A virus has only eight genes, so it is dependent on host proteins and pathways to mediate viral ribonucleoprotein (vRNP) trafficking and to promote vRNP functions at all stages of the virus life cycle. Here, Kawaoka and colleagues describe the trafficking and functions of influenza A vRNPs in host cells, emphasizing how vRNPs interact with and depend on host factors and pathways, how vRNP structure contributes to its function and the key open questions that still need to be answered.

Review Article | | Nature Reviews Microbiology

Current influenza vaccines are effective but require reformulation each year and do not protect against pandemic influenza strains. Here, Krammer and Palese discuss the advances in the design and production of seasonal and pandemic influenza virus vaccines, including novel vaccine constructs and adjuvants. Advances in the design of universal influenza vaccines are also presented.

Review Article | | Nature Reviews Drug Discovery

Recent developments in data acquisition and quantitative modelling allow evolutionary biologists to predict future processes. This Perspective reviews progress in understanding the evolutionary dynamics of systems such as microorganisms and cancer and discusses unifying concepts of predictive analysis.

Perspective | | Nature Ecology & Evolution

The recognition of influenza virus by multiple pattern recognition receptors initiates numerous defence mechanisms to control disease through their effects on antiviral resistance and disease tolerance. Here, the authors review these mechanisms and discuss how the treatment of influenza virus-initiated diseases should promote both of these protective strategies to improve host fitness.

Review Article | | Nature Reviews Immunology

Influenza is an infectious respiratory disease that, in humans, is caused by influenza A and influenza B viruses. This Primer discusses the biological features of influenza viruses, their effects on human and animal health and the mitigation strategies to reduce the burden of this disease.

Primer | | Nature Reviews Disease Primers

Influenza is an infectious respiratory disease that, in humans, is caused by influenza A and influenza B viruses. This PrimeView highlights some key preventive measures to stop its spread.

PrimeView | | Nature Reviews Disease Primers

Research

Influenza virus replication requires a close coupling of viral and cellular transcription so that the influenza virus polymerase can snatch 5′-capped primers from nascent Pol II transcripts for transcription priming. Stephen Cusack and colleagues now present a crystal structure of bat FluA polymerase bound to a Pol II C-terminal domain peptide-mimic. They show how the two polymerases interact and suggest that the interaction site could be targeted for antiviral drug development.

Letter | | Nature

Wendy Barclay and colleagues identify a previously unknown factor underlying the restricted host range of influenza virus. They show that the host protein ANP32A acts a species barrier to the function of avian virus polymerase in mammalian cells. Crucially, the mutation E627K in viral protein PB2, which allows ANP32 family proteins to support the avian virus polymerase, is known to be associated with increased virulence of avian viruses in mammals.

Letter | | Nature

Erwin Fodor and colleagues report the crystal structure of influenza C virus RNA polymerase, captured in a closed, pre-activation conformation. This closed conformation appears very different from previously reported crystal structures of influenza A and B virus polymerases, which contained the RNA promoter. Influenza C infects pigs and humans, but is rarer than the A and B viruses and causes a less severe form of flu. Comparison of the new structure with the previous RNA-bound structures identifies large conformational changes associated with RNA binding and activation, illustrating the flexibility of the influenza virus RNA polymerase.

Letter | | Nature

Human influenza viruses preferentially use α2,6-linked sialic acid (SA) containing receptors, whereas avian viruses preferentially bind α2,3-linked SA. Efficient airborne transmission of influenza viruses between humans is associated with use of α2,6-linked SA and not α2,3-linked SA. Using a loss-of-function approach in which a 2009 pandemic H1N1 influenza virus was engineered to bind α2,3-SA, Kanta Subbarao and colleagues show in ferrets that the soft palate is an important site for the switch of receptor usage to take place, and that this tissue rapidly selects for transmissible influenza virus with human receptor preference. Together with previously published data, this work suggests that analysis of the replicative fitness of influenza A viruses in the soft palate may be warranted in assessment of their pandemic potential.

Letter | | Nature

An analysis of more than 9,000 haemagglutinin sequences of human seasonal influenza viruses over a 12-year time period (2000–2012) shows that the global circulation patterns of A/H1N1 and B viruses differ markedly from those of the well characterized A/H3N2 viruses. In particular the H1N1 viruses persist locally across multiple seasons and don't show the same degree of global movement as the H3N2 viruses. The authors correlate these dynamics with rates of antigenic evolution, age of infection and size of epidemics.

Letter | | Nature

Yi Guan and colleagues trace the evolution and spread of H7N9 influenza virus during the second wave of the 2013 outbreak. They provide a large number of new H7N9 virus sequences from isolates collected during influenza surveillance throughout China spanning October 2013 and July 2014. They show that the virus has diverged into distinct clades, becoming established in chickens and it has disseminated to wider geographic regions. The manner in which H7N9 viruses have become established in the influenza ecosystem of China strongly suggest that this virus should be considered as a primary candidate to emerge as a pandemic strain in humans.

Letter | | Nature

Post-translational modifications of influenza A virus proteins can regulate virus replication, but the effect of nucleoprotein (NP) acetylation is not known. Here, Giese et al. identify four NP lysine residues that are acetylated in infected cells and study their role in polymerase activity and virion release.

Article | Open Access | | Nature Communications

Some circulating avian influenza A viruses can infect humans, but the mechanism enabling species jump is poorly understood. Here, Huanget al. identify a nucleotide in NEP of avian H7N9 viruses that affects splicing efficiency of the NS segment and supports virus replication in avian and mammalian cells.

Article | Open Access | | Nature Communications

Broadly reactive antibodies that recognize influenza A virus HA can be protective, but the mechanism is not completely understood. Here, He et al. show that the inflammatory response and phagocytosis mediated by the interaction between protective antibodies and macrophages are essential for protection.

Article | Open Access | | Nature Communications

A major goal of vaccine design is to protect against a broad range of pathogen strains. Here the authors isolate a new broadly neutralizing antibody against influenza haemagglutinin from human memory B cells, and identify mutations that increase and broaden the neutralization towards H5 HA subtype.

Article | Open Access | | Nature Communications

The 2009 H1N1 influenza pandemic exposed major gaps in our knowledge of the spatial ecology and evolution of swine influenza A viruses. Here Nelson et al. perform an extensive phylogenetic analysis of these viruses and show that the global trade of live swine strongly predicts their spatial dissemination.

Article | | Nature Communications

The availability of high-yield virus strains remains an important bottleneck in the rapid production of influenza vaccines. Here, the authors report the development of influenza A vaccine backbone that improves the virus yield of various seasonal and pandemic influenza vaccine strains in cell culture.

Article | Open Access | | Nature Communications

Antigenic drift and reassortment alters the epitopes of influenza virus. Krammer and colleagues reveal the cross-reactivity of antibody responses to viral hemagglutinin and neuraminidase in humans and several animal models, but the most prominent responses reflect ‘original antigenic sin’ to viral exposure.

Resource | | Nature Immunology

Humoral immunity is necessary for controlling viral infection. Ballesteros-Tato and colleagues show that development of follicular regulatory T cells is prevented by high concentrations of interleukin 2 at the peak of viral infection, but resumes at later time points to suppress autoantibody production.

Article | | Nature Immunology

IFITM3 encodes an antiviral protein that blocks entry of influenza A virus into cells. Paul Thomas and colleagues report that SNP rs34481144 in the 5′ UTR of IFITM3 is an expression quantitative trait locus for this gene and that the risk allele is associated with lower IFITM3 expression and severe influenza disease.

Article | | Nature Medicine

News & Comment

As we commemorate 100 years since the 1918 pandemic, research has advanced our knowledge of influenza virulence and pathogenesis, and has highlighted the role of animal reservoirs in the emergence of pandemic strains. Future efforts in understanding viral ecology, zoonosis and in integrating human and animal epidemiology should aid pandemic preparedness.

Comment | | Nature Reviews Microbiology

It is unclear why pregnant women are at high risk of severe influenza infection. Allogeneic pregnancy in mice is now shown to alter both innate and adaptive responses to influenza virus infection, enabling the emergence of more virulent virus variants.

News & Views | | Nature Microbiology

Influenza B virus causes substantial illness globally, particularly in children. Treatment options are limited, as the most widely used antiviral drug appears to be less effective than against influenza A. A new antibody targeting the influenza B neuraminidase shows promise in mice as a therapeutic option.

News & Views | | Nature Microbiology

The quest to improve influenza vaccines is aided by research into the immune response that they generate. Two recent studies have focused their attention on the specificities of antibodies induced after vaccination with conventional inactivated influenza vaccines.

News & Views | | Nature Medicine