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Review
. 2014 Apr;33(4):479-90.
doi: 10.1007/s10096-013-1984-8. Epub 2013 Sep 29.

Determinants of virulence of influenza A virus

E J A Schrauwen, M de Graaf, S Herfst, G F Rimmelzwaan, A D M E Osterhaus, R A M Fouchier
Review

Determinants of virulence of influenza A virus

E J A Schrauwen et al. Eur J Clin Microbiol Infect Dis. 2014 Apr.

Abstract

Influenza A viruses cause yearly seasonal epidemics and occasional global pandemics in humans. In the last century, four human influenza A virus pandemics have occurred. Occasionally, influenza A viruses that circulate in other species cross the species barrier and infect humans. Virus reassortment (i.e. mixing of gene segments of multiple viruses) and the accumulation of mutations contribute to the emergence of new influenza A virus variants. Fortunately, most of these variants do not have the ability to spread among humans and subsequently cause a pandemic. In this review, we focus on the threat of animal influenza A viruses which have shown the ability to infect humans. In addition, genetic factors which could alter the virulence of influenza A viruses are discussed. The identification and characterisation of these factors may provide insights into genetic traits which change virulence and help us to understand which genetic determinants are of importance for the pandemic potential of animal influenza A viruses.

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Conflict of interest statement

Conflict of interest

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1. Influenza A virus particle and replication cycle
A) Schematic representation of influenza A virus particle and gene segments. The influenza genome consists of eight single-stranded RNAs. The non-structural proteins and/or newly identified proteins with unknown function are depicted in rectangles. B) Schematic representation of an influenza A virus replication cycle. The viral HA binds to the appropriate host receptor and the virus enters via receptor-mediated endocytosis. A low-pH-triggered conformational change of HA mediates fusion between the viral en endosomal membrane and the RNPs are released into the cytoplasm. The RNPs trans-locate to the nucleus, where the vRNA transcription and replication takes place by the RNA-dependent RNA polymerases (PB1, PA and PB2). The mRNA is transported out of the nucleus and translated into the viral proteins. Viral proteins that are needed for replication and transcription are trans-located back into the nucleus. Newly synthesized vRNA, along with the polymerase proteins and NP, forms the vRNPs. M1 and NEP subsequently mediate transport of the newly synthesized vRNPs to the cytoplasm. At the plasma membrane, new virus particles are assembled and released via budding. Release from the host cell is mediated by NA, which cleaves off SA from cellular and viral glycoproteins so that the new virus particles can detach from the cell. Several influenza A proteins have been shown to be important determinants of virulence (indicated with boxes). The HA glycoprotein (light green) is important as a tropism factor, for cleavage of HA by cellular proteases, and is a prerequisite for starting viral infection. When some HAs are cleavable by ubiquitous proteases, this can result in systemic virus replication in some hosts (e.g. poultry). HA is also responsible for attachment to the different host cell receptors. The PB2 polymerase protein (light blue), has the ability to increase replication levels of vRNA in the nucleus. The PB1-F2 protein (grey) contributes to viral pathogenicity by inducing apoptosis of infected cells. The PA-X protein (orange) regulates the host-cell shut off. The NS1 protein (dark green) can counteract the innate immune response of the host. The NA protein (red) acts as a virulence factor by allowing efficient release of the virus particle from the cell. C) Schematic illustration of the vRNP structure. The viral RNA is encapsidated by NP, and this structure is bound to the polymerase complex (PB2, PB1 and PA).
Figure 2
Figure 2. Reassortment and adaptation events of pandemic influenza A viruses
For the 1918 H1N1 “Spanish influenza” pandemic, evidence for two scenarios has been presented: 1) the virus emerged upon reassortment between avian and mammalian influenza viruses and 2) the gradual adaptation of avian influenza genes to the human host. The 1918 H1N1 virus caused seasonal epidemics until 1957, when the H2N2 virus emerged upon re-assortment of the seasonal H1N1 with an avian H2N2 virus, thereby introducing the avian HA, NA, and PB1 genes. The H2N2 virus circulated in humans until 1968, when re-assortment of the H2N2 with an avian H3 virus resulted in the exchange of the H3 HA and PB1 genes and the generation of the H3N2 “Hong Kong” influenza. The pH1N1 virus consists of the NA and M genes of the Eurasian swine lineage, and the other genes of a “triple reassortant” swine influenza virus that had previously acquired its genes upon re-assortment between human, avian, and (classical) swine viruses. Grey colour in virus particles indicates uncertainty of viral gene segment origin or lack of data. Dotted arrows indicate uncertain scenarios and solid arrows indicate events that are supported by scientific evidence. Dashed arrows represent pandemic viruses circulating in subsequent influenza seasons. Partially adapted from [101].
Figure 3
Figure 3. Cleavage site as an important virulence factor
The HA0 is cleaved into two subunits HA1 and HA2 by cellular proteases which recognize either a mono basic or multi basic cleavage site. The HA0 of LPAI viruses harbors a mono basic cleavage site and is cleaved by trypsin-like proteases only, thereby limiting replication of these viruses to sites where these enzymes are expressed; i.e. respiratory and intestinal tract. The HA0 of HPAI viruses of the H5 and H7 subtype can be cleaved by ubiquitously expressed furin-like proteases, facilitating systemic replication in chickens.
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