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.
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.
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.
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.
Mortality from influenza viruses is strongly linked to secondary bacterial invaders. Here, Jonathan A. McCullers reviews viral and bacterial virulence factors that contribute to the pathogenesis of co-infections by disrupting physical barriers, dysregulating immune responses and delaying a return to homeostasis.
Enabling the 'host jump': structural determinants of receptor-binding specificity in influenza A viruses
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.
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.
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.
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.
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.
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.
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.
Broadly protective murine monoclonal antibodies against influenza B virus target highly conserved neuraminidase epitopes
This study reports the identification of broadly protective antibodies targeting the influenza B neuraminidase away from its active site. One dose of antibody therapy was more protective in mice than multiple doses of the current standard of care.
Influenza virus infection produces double-stranded RNA precursors that are converted to small interfering RNAs by host Dicer; this RNA interference mechanism is inhibited by viral protein NS1.
Influenza A virus polymerase has a β-hairpin in the thumb subdomain, which is shown to be essential for the initiation of viral replication, but auxiliary for other replicative steps and viral transcription.
Antigenic variants from human H1N1 and H3N2 influenza virus libraries possessing random mutations in the haemagglutinin protein, selected by incubation with human and/or ferret convalescent sera, identify escape variants similar to those that have emerged in nature.
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.
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.
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.
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.
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.
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.
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.
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.
Protein interaction networks can identify host proteins that affect virus replication. Here, the authors compare the protein interactomes of several influenza A virus strains and identify plakophilin 2 as a restriction factor that inhibits formation of the viral polymerase complex.
Alveolar macrophages are critical for broadly-reactive antibody-mediated protection against influenza A virus in mice
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.
The nucleotide sequence of the eight genomic RNA segments of influenza A virus provides essential packaging signals, but how these sequences are recognized is unknown. Here, Moreira et al. identify conserved amino acids in the viral nucleoprotein that regulate packaging of RNA segments.
Treatment of influenza A viruses with broadly neutralizing monoclonal antibodies is an area of active research. Here, the authors characterise a human monoclonal antibody called 3E1 that was reactive against both H1 and H5 viruses in vitroand demonstrated some treatment efficacy in mice.
A broadly neutralizing anti-influenza antibody reveals ongoing capacity of haemagglutinin-specific memory B cells to evolve
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.
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.
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.
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.
Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection
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.
Adjuvanted influenza-H1N1 vaccination reveals lymphoid signatures of age-dependent early responses and of clinical adverse events
Vaccination offers protection against infectious diseases, yet pre-existing criteria that predict vaccine efficacy or adverse events remain unknown. Hayday and colleagues identify cellular and molecular signatures in humans immunized with adjuvanted swine flu vaccine.
SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans
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.
Molecular-level analysis of the serum antibody repertoire in young adults before and after seasonal influenza vaccination
Antibodies that bind to both H1 and H3 influenza strains exist in the pre-vaccination serum repertoire of healthy adults; most vaccine-elicited clonotypes bind either H1 or H3 strains.
Antibodies elicited by vaccination with influenza vaccine produced in eggs bind more strongly to the egg-adapted vaccine strain than to wild-type circulating strains.
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.
Increasingly, the pathogens that pose the greatest threats to humans are those that evolve to escape prior immunity and pharmaceutical interventions. In response, we need to employ evolutionary thinking to manage infectious disease.
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.
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.
Clear links between human genes and susceptibility to influenza disease are scarce. A recent study uncovers a gene variant coupled to severe influenza, and shows how it hampers the expression of an antiviral gene that is key to immune cell survival.
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.