Key Points
-
Influenza A viruses are zoonotic viruses that can infect multiple hosts in nature, including birds, pigs, dogs, horses and humans. These viruses undergo substantial and constant reassortment in wild hosts, leading to the permanent possibility of the emergence of novel strains with epidemic or pandemic potential in humans.
-
Human cases of infection with the highly pathogenic avian influenza virus carrying the H5 subtype of haemagglutinin (HA) and the N1 subtype of neuraminidinase (NA) (H5N1) continue to occur throughout parts of East and Southeast Asia, the Middle East, Africa and Europe. Outbreaks of H7 and H9 viruses in poultry and zoonotic infections of humans with these viral strains, as well as the emergence in 2009 of a pandemic H1N1 strain that originated in pigs, revealed the need and the value of systematic surveillance of susceptible hosts.
-
Several viral adaptations are required for efficient infection, replication and transmission in a new host. In addition, several virus–host interactions modulate infection, and disease severity is a consequence of viral virulence determinants and host-specific responses to infection. Thus, the pathogenesis of influenza A viruses is multifactorial and host specific.
-
The level of pre-existing immunity in the general population is a major determinant of pathogenesis. The emergence of antigenically novel viruses as a result of immune selection pressure leads to regular epidemics. In addition, the acquisition (through reassortment) of a novel HA subtype or an HA that is antigenically similar to older strains but to which a large proportion of the population is naive (as was the case with the 2009 pandemic H1N1 strain) can lead to the emergence of a pandemic virus.
-
In humans, several underlying risk factors for infection have been identified. These include obesity, diabetes, cardiovascular disease, chronic lung disease (including asthma), pregnancy, old age, young age (<2 years) and being immunocompromised. Carefully designed clinical studies to elucidate the contribution of genetic susceptibility factors and polymorphisms, as well as to further define human susceptibility factors, are key for improving our understanding of the host determinants of influenza virus pathogenesis.
Abstract
Influenza A viruses are zoonotic pathogens that continuously circulate and change in several animal hosts, including birds, pigs, horses and humans. The emergence of novel virus strains that are capable of causing human epidemics or pandemics is a serious possibility. Here, we discuss the value of surveillance and characterization of naturally occurring influenza viruses, and review the impact that new developments in the laboratory have had on our understanding of the host tropism and virulence of viruses. We also revise the lessons that have been learnt from the pandemic viruses of the past 100 years.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to the full article PDF.
USD 39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Co-evolution of immunity and seasonal influenza viruses
Influenza A virus reassortment in mammals gives rise to genetically distinct within-host subpopulations
References
Molinari, N. A. et al. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine 25, 5086–5096 (2007).
Johnson, N. P. & Mueller, J. Updating the accounts: global mortality of the 1918–1920 “Spanish” influenza pandemic. Bull. Hist. Med. 76, 105–115 (2002).
Palese, P. & Shaw, M. L. in Fields Virology 5th edn (eds Knipe, D. M. et al.) 1647–1689 (Lippincott Williams & Wilkins, Philadelphia, USA, 2007).
Wise, H. M. et al. A complicated message: identification of a novel PB1-related protein translated from influenza A virus segment 2 mRNA. J. Virol. 83, 8021–8031 (2009).
Fouchier, R. A. et al. Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls. J. Virol. 79, 2814–2822 (2005).
Russell, R. J. et al. H1 and H7 influenza haemagglutinin structures extend a structural classification of haemagglutinin subtypes. Virology 325, 287–296 (2004).
Nobusawa, E. et al. Comparison of complete amino acid sequences and receptor-binding properties among 13 serotypes of hemagglutinins of influenza A viruses. Virology 182, 475–485 (1991).
Air, G. M. Sequence relationships among the hemagglutinin genes of 12 subtypes of influenza A virus. Proc. Natl Acad. Sci. USA 78, 7639–7643 (1981). A seminal study that has led to the current group and clade classification of influenza virus subtypes.
Wright, P. F., Neumann, G., & Kawaoka, Y. in Fields Virology 5th edn (eds Knipe, D. M. et al.) 1691–1740 (Lippincott Williams & Wilkins, Philadelphia, USA, 2007).
WHO. Pandemic (H1N1) 2009 - update 109. WHO Global Alert and Response [online], http://www.who.int/csr/don/2010_07_16/en/index.html (2009).
CDC. Updated CDC estimates of 2009 H1N1 influenza cases, hospitalizations and deaths in the United States, April 2009 – April 10, 2010. CDC [online], (2010).
Brown, I. H. Summary of avian influenza activity in Europe, Asia, and Africa, 2006–2009. Avian Dis. 54, 187–193 (2010).
Senne, D. A. Avian influenza in North and South America, the Caribbean, and Australia, 2006–2008. Avian Dis. 54, 179–186 (2010).
Krauss, S. et al. Influenza in migratory birds and evidence of limited intercontinental virus exchange. PLoS Pathog. 3, e167 (2007).
Obenauer, J. C. et al. Large-scale sequence analysis of avian influenza isolates. Science 311, 1576–1580 (2006). The first comprehensive sequencing and genomic analysis of AIVs, leading to the identification of the NS1 PDZ domain-binding motif.
Vijaykrishna, D. et al. Evolutionary dynamics and emergence of panzootic H5N1 influenza viruses. PLoS Pathog. 4, e1000161 (2008).
Claas, E. C. et al. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet 351, 472–477 (1998). A clinical study describing one of the first H5N1 influenza virus infections to be suggestive of a direct avian–human transmission.
WHO. Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO. WHO Global Alert and Response [online], (2011).
Li, K. S. et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature 430, 209–213 (2004).
WHO. Continuing progress towards a unified nomenclature system for the highly pathogenic H5N1 avian influenza viruses. WHO [online], (2009).
WHO/OIE/FAO H5N1 Evolution Working Group. Toward a unified nomenclature system for highly pathogenic avian influenza virus (H5N1). Emerg. Infect. Dis. 14, e1 (2008).
Jackson, D., Hossain, M. J., Hickman, D., Perez, D. R. & Lamb, R. A. A new influenza virus virulence determinant: the NS1 protein four C-terminal residues modulate pathogenicity. Proc. Natl Acad. Sci. USA 105, 4381–4386 (2008).
Dugan, V. G. et al. The evolutionary genetics and emergence of avian influenza viruses in wild birds. PLoS Pathog. 4, e1000076 (2008).
Chen, H. et al. Avian flu: H5N1 virus outbreak in migratory waterfowl. Nature 436, 191–192 (2005).
Chen, H. et al. Establishment of multiple sublineages of H5N1 influenza virus in Asia: implications for pandemic control. Proc. Natl Acad. Sci. USA 103, 2845–2850 (2006).
Smith, G. J. et al. Emergence and predominance of an H5N1 influenza variant in China. Proc. Natl Acad. Sci. USA 103, 16936–16941 (2006).
Fouchier, R. A. et al. Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc. Natl Acad. Sci. USA 101, 1356–1361 (2004).
Koopmans, M. et al. Transmission of H7N7 avian influenza A virus to human beings during a large outbreak in commercial poultry farms in the Netherlands. Lancet 363, 587–593 (2004). The original account of a highly pathogenic H7N7 influenza virus outbreak in humans that was produced by direct avian-to-human transmission.
Peiris, M. et al. Human infection with influenza H9N2. Lancet 354, 916–917 (1999).
Lin, Y. P. et al. Avian-to-human transmission of H9N2 subtype influenza A viruses: relationship between H9N2 and H5N1 human isolates. Proc. Natl Acad. Sci. USA 97, 9654–9658 (2000).
Malik Peiris, J. S. Avian influenza viruses in humans. Rev. Sci. Tech. 28, 161–173 (2009).
Kalthoff, D., Globig, A. & Beer, M. (Highly pathogenic) avian influenza as a zoonotic agent. Vet. Microbiol. 140, 237–245 (2010).
Dong, G. et al. Phylogenetic diversity and genotypical complexity of H9N2 influenza A viruses revealed by genomic sequence analysis. PLoS ONE 6, e17212 (2011).
Xu, K. M. et al. The genesis and evolution of H9N2 influenza viruses in poultry from southern China, 2000 to 2005. J. Virol. 81, 10389–10401 (2007).
Song, X. F., Han, P. & Chen, Y. P. Genetic variation of the hemagglutinin of avian influenza virus H9N2. J. Med. Virol. 83, 838–846 (2011).
Bulach, D. et al. Molecular analysis of H7 avian influenza viruses from Australia and New Zealand: genetic diversity and relationships from 1976 to 2007. J. Virol. 84, 9957–9966 (2010).
Munster, V. J. et al. Mallards and highly pathogenic avian influenza ancestral viruses, northern Europe. Emerg. Infect. Dis. 11, 1545–1551 (2005).
Rambaut, A. et al. The genomic and epidemiological dynamics of human influenza A virus. Nature 453, 615–619 (2008). A comprehensive phylogeographical analysis that led to the proposal of the 'sink–source' model of influenza virus epidemics.
Nelson, M. I. et al. Multiple reassortment events in the evolutionary history of H1N1 influenza A virus since 1918. PLoS Pathog. 4, e1000012 (2008).
Holmes, E. C. et al. Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses. PLoS Biol. 3, e300 (2005).
Nelson, M. I. et al. Stochastic processes are key determinants of short-term evolution in influenza a virus. PLoS Pathog. 2, e125 (2006).
Russell, C. A. et al. The global circulation of seasonal influenza A (H3N2) viruses. Science 320, 340–346 (2008). A genetic and antigenic analysis of human seasonal H3N2 viruses, demonstrating the dominant seeding characteristics of these viruses that originated from local epidemics in West and Southeast Asia.
Nelson, M. I., Simonsen, L., Viboud, C., Miller, M. A. & Holmes, E. C. Phylogenetic analysis reveals the global migration of seasonal influenza A viruses. PLoS Pathog. 3, 1220–1228 (2007).
Lowen, A. C., Mubareka, S., Steel, J. & Palese, P. Influenza virus transmission is dependent on relative humidity and temperature. PLoS Pathog. 3, 1470–1476 (2007).
CDC. Update: influenza activity - United States, 2009–2010 season. MMWR Morb. Mortal. Wkly Rep. 59, 901–908 (2010).
Zepeda-Lopez, H. M. et al. Inside the outbreak of the 2009 influenza A (H1N1)v virus in Mexico. PLoS ONE 5, e13256 (2010).
Chao, D. L., Halloran, M. E. & Longini, I. M. Jr. School opening dates predict pandemic influenza A(H1N1) outbreaks in the United States. J. Infect. Dis. 202, 877–880 (2010).
Fraser, C. et al. Pandemic potential of a strain of influenza A (H1N1): early findings. Science 324, 1557–1561 (2009).
Garten, R. J. et al. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 325, 197–201 (2009).
Smith, G. J. et al. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature 459, 1122–1125 (2009). References 49 and 50 present two detailed genetic, phylogenetic and coalescent-based analyses demonstrating the complex reassortment history and genesis of the 2009 pandemic H1N1 virus.
Kuiken, T. et al. Host species barriers to influenza virus infections. Science 312, 394–397 (2006). An excellent review on the host, viral and environmental factors that affect and contribute to host tropism.
Stevens, J. et al. Glycan microarray analysis of the hemagglutinins from modern and pandemic influenza viruses reveals different receptor specificities. J. Mol. Biol. 355, 1143–1155 (2006).
Chandrasekaran, A. et al. Glycan topology determines human adaptation of avian H5N1 virus hemagglutinin. Nature Biotech. 26, 107–113 (2008). The first demonstration that the size and shape of SA-containing receptors can modulate the receptor-binding properties of influenza A viruses.
Matrosovich, M., Zhou, N., Kawaoka, Y. & Webster, R. The surface glycoproteins of H5 influenza viruses isolated from humans, chickens, and wild aquatic birds have distinguishable properties. J. Virol. 73, 1146–1155 (1999).
Shinya, K. et al. Avian flu: influenza virus receptors in the human airway. Nature 440, 435–436 (2006).
van Riel, D. et al. H5N1 virus attachment to lower respiratory tract. Science 312, 399 (2006).
Ito, T. et al. Molecular basis for the generation in pigs of influenza A viruses with pandemic potential. J. Virol. 72, 7367–7373 (1998).
Smith, G. J. et al. Dating the emergence of pandemic influenza viruses. Proc. Natl Acad. Sci. USA 106, 11709–11712 (2009).
Kimble, B., Nieto, G. R. & Perez, D. R. Characterization of influenza virus sialic acid receptors in minor poultry species. Virol. J. 7, 365 (2010).
Wan, H. & Perez, D. R. Quail carry sialic acid receptors compatible with binding of avian and human influenza viruses. Virology 346, 278–286 (2006).
Soundararajan, V. et al. Extrapolating from sequence—the 2009 H1N1 'swine' influenza virus. Nature Biotech. 27, 510–513 (2009).
Chen, L. M. et al. Receptor specificity of subtype H1 influenza A viruses isolated from swine and humans in the United States. Virology 412, 401–410 (2011).
Childs, R. A. et al. Receptor-binding specificity of pandemic influenza A (H1N1) 2009 virus determined by carbohydrate microarray. Nature Biotech. 27, 797–799 (2009). A study showing the binding activity of the 2009 pandemic H1N1 virus with respect to SA specificity.
Munster, V. J. et al. Pathogenesis and transmission of swine-origin 2009 A(H1N1) influenza virus in ferrets. Science 325, 481–483 (2009).
Maines, T. R. et al. Transmission and pathogenesis of swine-origin 2009 A(H1N1) influenza viruses in ferrets and mice. Science 325, 484–487 (2009).
Nicholls, J. M. et al. Tropism of avian influenza A (H5N1) in the upper and lower respiratory tract. Nature Med. 13, 147–149 (2007).
Maines, T. R. et al. Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model. Proc. Natl Acad. Sci. USA 103, 12121–12126 (2006).
Srinivasan, A. et al. Quantitative biochemical rationale for differences in transmissibility of 1918 pandemic influenza A viruses. Proc. Natl Acad. Sci. USA 105, 2800–2805 (2008).
Tumpey, T. M. et al. A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission. Science 315, 655–659 (2007). The demonstration that the transmission of influenza A virus can be modulated by receptor-binding specificity.
Steel, J., Lowen, A. C., Mubareka, S. & Palese, P. Transmission of influenza virus in a mammalian host is increased by PB2 amino acids 627K or 627E/701N. PLoS Pathog. 5, e1000252 (2009).
Stevens, J. et al. Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 312, 404–410 (2006). The first crystal structure of the HA of a HPAI virus.
Yamada, S. et al. Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature 444, 378–382 (2006). A study that elucidates the specific residues needed for the avian H5N1 influenza viruses to switch from avian to human SA specificity.
Gao, Y. et al. Identification of amino acids in HA and PB2 critical for the transmission of H5N1 avian influenza viruses in a mammalian host. PLoS Pathog. 5, e1000709 (2009).
Russell, R. J., Stevens, D. J., Haire, L. F., Gamblin, S. J. & Skehel, J. J. Avian and human receptor binding by hemagglutinins of influenza A viruses. Glycoconj. J. 23, 85–92 (2006).
Xu, R., McBride, R., Paulson, J. C., Basler, C. F. & Wilson, I. A. Structure, receptor binding, and antigenicity of influenza virus hemagglutinins from the 1957 H2N2 pandemic. J. Virol. 84, 1715–1721 (2010).
Liu, J. et al. Structures of receptor complexes formed by hemagglutinins from the Asian Influenza pandemic of 1957. Proc. Natl Acad. Sci. USA 106, 17175–17180 (2009).
Chan, P. K. et al. Clinical and virological course of infection with haemagglutinin D222G mutant strain of 2009 pandemic influenza A (H1N1) virus. J. Clin. Virol. 50, 320–324 (2011).
Kilander, A., Rykkvin, R., Dudman, S. G. & Hungnes, O. Observed association between the HA1 mutation D222G in the 2009 pandemic influenza A(H1N1) virus and severe clinical outcome, Norway 2009–2010. Euro Surveill. 15, 19498 (2010).
Chutinimitkul, S. et al. Virulence-associated substitution D222G in the hemagglutinin of 2009 pandemic influenza A(H1N1) virus affects receptor binding. J. Virol. 84, 11802–11813 (2010).
Liu, Y. et al. Altered receptor specificity and cell tropism of D222G hemagglutinin mutants isolated from fatal cases of pandemic A(H1N1) 2009 influenza virus. J. Virol. 84, 12069–12074 (2010).
Itoh, Y. et al. In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses. Nature 460, 1021–1025 (2009). A report describing comprehensive in vitro and in vivo studies of the 2009 pandemic H1N1 virus strain, characterizing its pathogenicity, drug susceptibility and human antibody cross reactivity.
Manicassamy, B. et al. Protection of mice against lethal challenge with 2009 H1N1 influenza a virus by 1918-like and classical swine H1N1 based vaccines. PLoS Pathog. 6, e1000745 (2010). The first study to demonstrate the close antigenic similarities between the 2009 and 1918 pandemic H1N1 viruses.
Salomon, R. et al. The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04. J. Exp. Med. 203, 689–697 (2006).
Subbarao, E. K., London, W. & Murphy, B. R. A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J. Virol. 67, 1761–1764 (1993). A seminal work which demonstrates that residue K627 of PB2 is an adaptation to the human host.
Hatta, M. et al. Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice. PLoS Pathog. 3, 1374–1379 (2007).
de Wit, E. et al. Molecular determinants of adaptation of highly pathogenic avian influenza H7N7 viruses to efficient replication in the human host. J. Virol. 84, 1597–1606 (2010).
Gabriel, G. et al. The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host. Proc. Natl Acad. Sci. USA 102, 18590–18595 (2005).
de Jong, M. D. et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nature Med. 12, 1203–1207 (2006). A study showing a correlation between increased viral titres and potent immune responses (in the form of a cytokine storm) in fatal cases of human infection with HPAI H5N1 virus.
Van Hoeven, N. et al. Human HA and polymerase subunit PB2 proteins confer transmission of an avian influenza virus through the air. Proc. Natl Acad. Sci. USA 106, 3366–3371 (2009).
Perez, D. R. et al. Fitness of pandemic H1N1 and seasonal influenza A viruses during co-infection: evidence of competitive advantage of pandemic H1N1 influenza versus seasonal influenza. PLoS Curr. 1, RRN1011 (2009). A timely study that demonstrates the in vivo infection dynamics of the 2009 pandemic H1N1 virus as compared with the dynamics of sesonal H1N1 and the H3N2 viruses.
Mehle, A. & Doudna, J. A. Adaptive strategies of the influenza virus polymerase for replication in humans. Proc. Natl Acad. Sci. USA 106, 21312–21316 (2009).
Yamada, S. et al. Biological and structural characterization of a host-adapting amino acid in influenza virus. PLoS Pathog. 6 e1001034 (2010).
Hao, L. et al. Drosophila RNAi screen identifies host genes important for influenza virus replication. Nature 454, 890–893 (2008).
Konig, R. et al. Human host factors required for influenza virus replication. Nature 463, 813–817 (2010).
Shapira, S. D. et al. A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection. Cell 139, 1255–1267 (2009).
Karlas, A. et al. Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication. Nature 463, 818–822 (2010).
Brass, A. L. et al. The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell 139, 1243–1254 (2009).
Watanabe, T., Watanabe, S. & Kawaoka, Y. Cellular networks involved in the influenza virus life cycle. Cell Host Microbe 7, 427–439 (2010). A comprehensive review summarizing the key findings of five large genome-wide studies (references 92–96) that identified host factors which are required at different stages of influenza virus replication.
Yount, J. S. et al. Palmitoylome profiling reveals S-palmitoylation-dependent antiviral activity of IFITM3. Nature Chem. Biol. 6, 610–614 (2010).
Tumpey, T. M. et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 310, 77–80 (2005). The first study to describe the increased pathogenesis of the extinct 1918 pandemic H1N1 virus (reconstructed from plasmid DNA).
Dawood, F. S. et al. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N. Engl. J. Med. 360, 2605–2615 (2009). The original article from the US CDC reporting the detection of the novel swine origin 2009 H1N1 influenza virus that resulted in the first influenza pandemic of the twenty-first century.
Hancock, K. et al. Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus. N. Engl. J. Med. 361, 1945–1952 (2009). A seroprevalence study which shows that individuals who were>65 years of age in 2009 had a considerable level of cross-reactive antibodies against the 2009 H1N1 virus, indicative of previous exposure to an older, antigenically similar virus.
Skountzou, I. et al. Immunity to pre-1950 H1N1 influenza viruses confers cross-protection against the pandemic swine-origin 2009 A (H1N1) influenza virus. J. Immunol. 185, 1642–1649 (2010).
Kash, J. C. et al. Prior infection with classical swine H1N1 influenza viruses is associated with protective immunity to the 2009 pandemic H1N1 virus. Influenza Other Respi. Viruses 4, 121–127 (2010).
Medina, R. A. et al. Pandemic 2009 H1N1 vaccine protects against 1918 Spanish influenza virus. Nature Commun. 1, 28 (2010).
Xu, R. et al. Structural basis of preexisting immunity to the 2009 H1N1 pandemic influenza virus. Science 328, 357–360 (2010).
Wei, C. J. et al. Cross-neutralization of 1918 and 2009 influenza viruses: role of glycans in viral evolution and vaccine design. Sci. Transl. Med. 2, 24ra21 (2010).
Wang, C. C. et al. Glycans on influenza hemagglutinin affect receptor binding and immune response. Proc. Natl Acad. Sci. USA 106, 18137–18142 (2009).
Jang, H. et al. Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc. Natl Acad. Sci. USA 106, 14063–14068 (2009).
Kobasa, D. et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 445, 319–323 (2007). This work shows that increased immune responses exacerbate and contribute to the pathogenesis of the 1918 H1N1 virus in non-human primates.
Watanabe, T. et al. Viral RNA polymerase complex promotes optimal growth of 1918 virus in the lower respiratory tract of ferrets. Proc. Natl Acad. Sci. USA 106, 588–592 (2009).
Pappas, C. et al. Single gene reassortants identify a critical role for PB1, HA, and NA in the high virulence of the 1918 pandemic influenza virus. Proc. Natl Acad. Sci. USA 105, 3064–3069 (2008).
Gibbs, J. S., Malide, D., Hornung, F., Bennink, J. R. & Yewdell, J. W. The influenza A virus PB1-F2 protein targets the inner mitochondrial membrane via a predicted basic amphipathic helix that disrupts mitochondrial function. J. Virol. 77, 7214–7224 (2003).
Chen, W. et al. A novel influenza A virus mitochondrial protein that induces cell death. Nature Med. 7, 1306–1312 (2001). The first identification of the PB1-F2 protein, which is encoded by a second ORF of the PB1 segment in influenza A viruses.
Zamarin, D., Garcia-Sastre, A., Xiao, X., Wang, R. & Palese, P. Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog. 1, e4 (2005).
Conenello, G. M., Zamarin, D., Perrone, L. A., Tumpey, T. & Palese, P. A single mutation in the PB1-F2 of H5N1 (HK/97) and 1918 influenza A viruses contributes to increased virulence. PLoS Pathog. 3, 1414–1421 (2007).
McAuley, J. L. et al. Expression of the 1918 influenza A virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia. Cell Host Microbe 2, 240–249 (2007). A study showing that PB1-F2 promotes secondary bacterial infection, thus increasing influenza A virus pathogenesis.
Varga, Z. T. et al. The influenza virus protein PB1-F2 inhibits the induction of type I interferon at the level of the MAVS adaptor protein. PLoS Pathog. 7, e1002067 (2011).
Hai, R. et al. PB1-F2 expression by the 2009 pandemic H1N1 influenza virus has minimal impact on virulence in animal models. J. Virol. 84, 4442–4450 (2010).
McAuley, J. L. et al. PB1-F2 proteins from H5N1 and 20 century pandemic influenza viruses cause immunopathology. PLoS Pathog. 6, e1001014 (2010).
Hale, B. G., Randall, R. E., Ortin, J. & Jackson, D. The multifunctional NS1 protein of influenza A viruses. J. Gen. Virol. 89, 2359–2376 (2008). A thorough review discussing the many functions and properties of the NS1 protein of influenza viruses.
Gack, M. U. et al. Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe 5, 439–449 (2009).
Fernandez-Sesma, A. et al. Influenza virus evades innate and adaptive immunity via the NS1 protein. J. Virol. 80, 6295–6304 (2006).
Nemeroff, M. E., Barabino, S. M., Li, Y., Keller, W. & Krug, R. M. Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3'end formation of cellular pre-mRNAs. Mol. Cell 1, 991–1000 (1998).
Beigel, J. H. et al. Avian influenza A (H5N1) infection in humans. N. Engl. J. Med. 353, 1374–1385 (2005).
Seo, S. H., Hoffmann, E. & Webster, R. G. Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nature Med. 8, 950–954 (2002).
Hale, B. G. et al. Mutations in the NS1 C-terminal tail do not enhance replication or virulence of the 2009 pandemic H1N1 influenza A virus. J. Gen. Virol. 91, 1737–1742 (2010).
Hale, B. G. et al. Inefficient control of host gene expression by the 2009 pandemic H1N1 influenza A virus NS1 protein. J. Virol. 84, 6909–6922 (2010).
Kash, J. C. et al. Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature 443, 578–581 (2006). The first global analysis of the host response to an in vivo infection (in mice) with the reconstructed 1918 pandemic H1N1 virus.
Perrone, L. A., Plowden, J. K., Garcia-Sastre, A., Katz, J. M. & Tumpey, T. M. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog. 4, e1000115 (2008).
Cilloniz, C. et al. Lethal influenza virus infection in macaques is associated with early dysregulation of inflammatory related genes. PLoS Pathog. 5, e1000604 (2009).
Baskin, C. R. et al. Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus. Proc. Natl Acad. Sci. USA 106, 3455–3460 (2009).
Nakamura, R. et al. Interleukin-15 is critical in the pathogenesis of influenza a virus-induced acute lung injury. J. Virol. 84, 5574–5582 (2010).
Crowe, C. R. et al. Critical role of IL-17RA in immunopathology of influenza infection. J. Immunol. 183, 5301–5310 (2009).
Herold, S. et al. Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand. J. Exp. Med. 205, 3065–3077 (2008).
Perrone, L. A., Szretter, K. J., Katz, J. M., Mizgerd, J. P. & Tumpey, T. M. Mice lacking both TNF and IL-1 receptors exhibit reduced lung inflammation and delay in onset of death following infection with a highly virulent H5N1 virus. J. Infect. Dis. 202, 1161–1170 (2010).
Sun, K., Torres, L. & Metzger, D. W. A detrimental effect of interleukin-10 on protective pulmonary humoral immunity during primary influenza A virus infection. J. Virol. 84, 5007–5014 (2010).
Sun, J., Madan, R., Karp, C. L. & Braciale, T. J. Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nature Med. 15, 277–284 (2009).
Salomon, R., Hoffmann, E. & Webster, R. G. Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. Proc. Natl Acad. Sci. USA 104, 12479–12481 (2007).
Manicassamy, B. et al. Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus. Proc. Natl Acad. Sci. USA 107, 11531–11536 (2010). The demonstration that natural killer cells, B cells and antigen-presenting cells, in addition to epithelial cells, are susceptible to influenza A virus infection in vivo .
WHO. Clinical features of severe cases of pandemic influenza. Pandemic (H1N1) 2009 briefing note 13. WHO Global Alert and Response [online], (2009).
Rothberg, M. B. & Haessler, S. D. Complications of seasonal and pandemic influenza. Crit. Care Med. 38, e91–e97 (2010).
Carcione, D. et al. Comparison of pandemic (H1N1) 2009 and seasonal influenza, Western Australia, 2009. Emerg. Infect. Dis. 16, 1388–1395 (2010).
Peiris, J. S., Poon, L. L. & Guan, Y. Emergence of a novel swine-origin influenza A virus (S-OIV) H1N1 virus in humans. J. Clin. Virol. 45, 169–173 (2009).
Monsalvo, A. C. et al. Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes. Nature Med. 17, 195–199 (2010). An interesting study that correlates the severity of disease seen in some middle-aged individuals infected with the 2009 pandemic H1N1 virus and the presence of immune complexes in their lungs.
Le, Q. M. et al. Avian flu: isolation of drug-resistant H5N1 virus. Nature 437, 1108 (2005).
Lemey, P., Suchard, M. & Rambaut, A. Reconstructing the initial global spread of a human influenza pandemic: a Bayesian spatial-temporal model for the global spread of H1N1pdm. PLoS Curr. 1, RRN1031 (2009). An original study showing the worldwide geographical spread of the 2009 H1N1 virus during the first 4 months of the pandemic outbreak.
Rambaut, A. & Holmes, E. The early molecular epidemiology of the swine-origin A/H1N1 human influenza pandemic. PLoS Curr. 1, RRN1003 (2009).
Jombart, T., Eggo, R. M., Dodd, P. & Balloux, F. Spatiotemporal dynamics in the early stages of the 2009 A/H1N1 influenza pandemic. PLoS Curr. 1, RRN1026 (2009).
Nelson, M. et al. The early diversification of influenza A/H1N1pdm. PLoS Curr. 1, RRN1126 (2009).
Vijaykrishna, D. et al. Reassortment of pandemic H1N1/2009 influenza A virus in swine. Science 328, 1529 (2010).
Vijaykrishna, D. et al. Long-term evolution and transmission dynamics of swine influenza A virus. Nature 473, 519–522 (2011). The first large-scale, systematic longitudinal surveillance study of swine influenza A viruses, which shows that reassortment contributes to the emergence of antigenic-drift lineages.
Perez, J. T. et al. Influenza A virus-generated small RNAs regulate the switch from transcription to replication. Proc. Natl Acad. Sci. USA 107, 11525–11530 (2010). A study showing the generation and accumulation of a small viral RNA that seems to regulate the switch from transcription to replication in influenza viruses during infection.
Umbach, J. L., Yen, H. L., Poon, L. L. & Cullen, B. R. Influenza a virus expresses high levels of an unusual class of small viral leader RNAs in infected cells. mBio 1, e00204–e00210 (2010).
Acknowledgements
We thank B. Hale for comments on the manuscript and E. Nistal-Villan for help with the crystal structure models in figure 2. Work in the A.G.-S. laboratory is supported by US National Institute of Allergy and Infectious Disease (NIAID) grants R01AI046954, U01AI070469, U19AI083025, U54AI057158 and P01AI058113; by the Center for Research of Influenza Pathogenesis (CRIP) — an NIAID-funded Center of Excellence for Influenza Research and Surveillance — (HHSN266200700010C); and by the W. M. Keck Foundation.
Ethics declarations
Competing interests
Adolfo García-Sastre reports a financial interest with Vivaldi BioScience and is also involved with patents filed through the Mount Sinai School of Medicine that are related to plasmid-based rescue of influenza virus and antiviral targets for influenza treatments. Rafael A. Medina declares no competing financial interests.
Related links
Related links
FURTHER INFORMATION
Adolfo García-Sastre's homepage
Food and Agriculture Organization of the United Nations, Animal Production and Health Division
National Institute of Allergy and Infectious Diseases Influenza Genome Sequencing Project
WHO Global Alert and Response Influenza
World Organization for Animal Health (OIE) Update on Avian Influenza
Glossary
- Reassortment
-
The exchange of segments of the viral genome between two distinct virus strains.
- Clades
-
Groups of biological taxa or species, the members of which share homologous features that were inherited from a common ancestor.
- Antigenic drift
-
A gradual change in genotype that is due to antibody-mediated immune selection pressure driving the accumulation of mutations.
- Antigenic shift
-
The reassortment of viral genomes, leading to the generation of a new subtype with a dramatic change in antigenic potential.
- Genotype
-
The classification of an influenza A virus subtype based on the genetic characteristics of the eight gene segments.
- Zoonotic
-
Pertaining to an infectious disease: originating in non-human animals, both wild and domestic, and able to be transmitted from those animals to humans.
- Coalescent analysis
-
A retrospective study of a genetic population (in this case, the influenza A virus genomes or segments), allowing all the alleles of each gene in question to be traced to a single ancestral gene.
- Nasopharyngeal
-
Pertaining to the area near the nasopharynx, which is the area of the upper throat that lies behind the nose.
- Oropharyngeal
-
Pertaining to the area near the oropharynx, which is the area of the upper throat that lies behind the mouth.
- Spillover
-
Infection of a distinct host by an infected natural host reservoir.
- Immune complex
-
A cluster of antibodies bound to a soluble antigen. These can cause disease if they are deposited in organs where they lead to tissue damage.
Rights and permissions
About this article
Cite this article
Medina, R., García-Sastre, A. Influenza A viruses: new research developments. Nat Rev Microbiol 9, 590–603 (2011). https://doi.org/10.1038/nrmicro2613
Published:
Issue date:
DOI: https://doi.org/10.1038/nrmicro2613
Share this article
Anyone you share the following link with will be able to read this content:
Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative
This article is cited by
-
Transcriptome-wide 5-methylcytosine modification profiling of long non-coding RNAs in A549 cells infected with H1N1 influenza A virus
BMC Genomics (2023)
-
A nomogram based on the expression level of angiopoietin-like 4 to predict the severity of community-acquired pneumonia
BMC Infectious Diseases (2023)
-
When influenza viruses don’t play well with others
Nature (2023)
-
Microbiota composition in the lower respiratory tract is associated with severity in patients with acute respiratory distress by influenza
Virology Journal (2023)
-
RUNX1 inhibits the antiviral immune response against influenza A virus through attenuating type I interferon signaling
Virology Journal (2022)
